Azabenzofuran substituted thioureas; inhibitors of viral replication

ABSTRACT

The present invention provides compounds of Formula 1,  
                 
 
wherein the variables Ar, A 1 , A 2 , A 3 , A 4 , R 5 , R 6 , R 7 , V, W. X, and Y are defined herein. 
Certain compounds of Formula 1 described herein possess potent antiviral activity. The invention also provides compounds of Formula 1 that are potent and/or selective inhibitors of Hepatitis C virus replication. The invention also provides pharmaceutical compositions containing one or more compounds of Formula 1, or a salt, solvate, or acylated prodrug of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents. The invention further comprises methods of treating patients suffering from certain infectious diseases by administering to such patients an amount of a compound of Formula 1 effective to reduce signs or symptoms of the disease. These infectious diseases include viral infections, particularly HCV infections. The invention is particularly includes methods of treating human patients suffering from an infectious disease, but also encompasses methods of treating other animals, including livestock and domesticated companion animals, suffering from an infectious disease. Methods of treatment include administering a compound of Formula 1 as a single active agent or administering a compound of Formula 1 in combination with on or more other therapeutic agent.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. provisional application60/534,839 filed Jan. 6, 2003, which is hereby incorporated in itsentirety.

FIELD OF THE INVENTION

The present invention provides azabenzofuran substituted thioureacompounds, particularly furanylpyridinyl substituted thioureaderivatives and related compounds, useful as antiviral agents. Certainazabenzofuran substituted thiourea compounds, including furanylpyridinylsubstituted thiourea compounds disclosed herein are potent and/orselective inhibitors of viral replication, particularly Hepatitis Cvirus replication. The invention also provides pharmaceuticalcompositions containing one or more azabenzofuran substituted thioureacompounds and one or more pharmaceutically acceptable carriers,excipients, or diluents. Such pharmaceutical compositions may contain anazabenzofuran substituted thiourea compound as the only active agent ormay contain a combination of an azabenzofuran substituted thioureacompound and one or more other pharmaceutically active agents. Theinvention also provides methods for treating Hepatitis C viralinfections in mammals.

BACKGROUND

In the 1940's the disease originally referred to as viral hepatitis wasdistinguished into two separate disorders termed infectious hepatitis(hepatitis A, HAV) and homologous serum hepatitis (hepatitis B, HBV).Transfusion of blood products had been demonstrated to be a common routeof transmission of viral hepatitis. HBV was originally assumed to be thecausative agent of post-transfusion hepatitis as the epidemiological andclinical features of the disorder did not fit those of HAV.

Soon after a radioimmunoassay for hepatitis B surface antigen (HBsAg)became available as a tool for identifying patients infected with HBV,it became apparent that most patients having post-transfusion hepatitiswere negative for HbsAg. Thus, hepatitis following blood transfusionthat was not caused by hepatitis A or hepatitis B and was subsequentlyreferred to as non-A, non-B hepatitis.

The causative agent of non-A, non-B hepatitis (hepatitis C virus, HCV)was discovered in 1989 via screening of cDNA expression libraries madefrom RNA and DNA from chimpanzees infected with serum from a patientwith post-transfusion non-A, non-B hepatitis. To identify portions ofthe genome that encoded viral proteins, the libraries were screened withantibodies from patients who had non-A, non-B hepatitis. Theseinvestigators went on to show that the virus they identified wasresponsible for the vast majority of cases of non-A, non-B hepatitis.

The hepatitis C virus is one of the most prevalent causes of chronicliver disease in the United States. It accounts for about 15 percent ofacute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to50 percent of cirrhosis, end-stage liver disease, and liver cancer.Almost 4 million Americans, or 1.8 percent of the U.S. population, haveantibodies to HCV (anti-HCV), indicating ongoing or previous infectionwith the virus. Hepatitis C causes an estimated 8,000 to 10,000 deathsannually in the United States. Hepatitis C virus (HCV) infection occursthroughout the world, and, prior to its identification, represented themajor cause of transfusion-associated hepatitis. The seroprevalence ofanti-HCV in blood donors from around the world has been shown to varybetween 0.02% and 1.23%. HCV is also a common cause of hepatitis inindividuals exposed to blood products. There have been an estimated150,000 new cases of HCV infection each year in the United States aloneduring the past decade.

The acute phase of HCV infection is usually associated with mildsymptoms. However, evidence suggests that only 15%-20% of the infectedpeople will clear HCV. Among the group of chronically infected people,10-20% will progress to life-threatening conditions known as cirrhosisand another 1-5% will develop a liver cancer called hepatocellularcarcinoma. Unfortunately, the entire infected population is at risk forthese life-threatening conditions because no one can predict whichindividual will eventually progress to any of them.

HCV is a small, enveloped, single-stranded positive RNA virus in theFlaviviridae family. The genome is approximately 10,000 nucleotides andencodes a single polyprotein of about 3,000 amino acids. The polyproteinis processed by host cell and viral proteases into three majorstructural proteins and several non-structural proteins necessary forviral replication. Several different genotypes of HCV with slightlydifferent genomic sequences have since been identified that correlatewith differences in response to treatment with interferon alpha.

HCV replicates in infected cells in the cytoplasm, in close associationwith the endoplasmic reticulum. Incoming positive sense RNA is releasedand translation is initiated via an internal initiation mechanism.Internal initiation is directed by a cis-acting RNA element at the 5′end of the genome; some reports have suggested that full activity ofthis internal ribosome entry site, or IRES, is seen with the first 700nucleotides, which spans the 5′ untranslated region (UTR) and the first123 amino acids of the open reading frame (ORF). All the proteinproducts of HCV are produced by proteolytic cleavage of a large(approximately 3000 amino acid) polyprotein, carried out by one of threeproteases: the host signal peptidase, the viral self-cleavingmetalloproteinase, NS2, or the viral serine protease NS3/4A . Thecombined action of these enzymes produces the structural proteins (C, E1and E2) and non-structural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B)proteins that are required for replication and packaging of viralgenomic RNA. NS5B is the viral RNA-dependent RNA polymerase (RDRP) thatis responsible for the conversion of the input genomic RNA into anegative stranded copy (complimentary RNA, or cRNA; the cRNA then servesas a template for transcription by NS5B of more positive sensegenomic/messenger RNA.

An effective vaccine is greatly needed, yet development is unlikely inthe near future because: i) lack of an efficient cell culture system andsmall animal models; ii) a weak neutralizing humoral and protectivecellular imnmune response; iii) marked genetic variability of the virus,and iv) the lack of a viral proofreading mechanism.

Several institutions and laboratories are attempting to identify anddevelop anti-HCV drugs. Currently the only effective therapy against HCVis alpha-interferon, which reduces the amount of virus in the liver andblood (viral load) in only a small proportion of infected patients.Alpha interferon was first approved for use in HCV treatment more thanten years ago. Alpha interferon is a host protein that is made inresponse to viral infections and has natural antiviral activity. Thesestandard forms of interferon, however, are now being replaced bypegylated interferons (peginterferons). Peginterferon is alphainterferon that has been modified chemically by the addition of a largeinert molecule of polyethylene glycol. At the present time, the optimalregimen appears to be a 24- or 48-week course of the combination ofpegylated alpha interferon and the nucleoside Ribavarin, an oralantiviral agent that has activity against a broad range of viruses. Byitself, Ribavarin has little effect on HCV, but adding it to interferonincreases the sustained response rate by two- to three-fold.Nonetheless, response rates to the combination interferon/Ribavarintherapy are moderate, in the range 50-60%, although response rates forselected genotypes of HCV (notably genotypes 2 and 3) are typicallyhigher. Among patients who become HCV RNA negative during treatment, asignificant proportion relapse when therapy is stopped.

In addition, there are often significant adverse side effects associatedwith each of these agents. Patients receiving interferon often presentwith flu-like symptoms. Pegylated interferon has been associated withbone marrow suppressive effects. Importantly, alpha interferon hasmultiple neuropsychiatric effects. Prolonged therapy can cause markedirritability, anxiety, personality changes, depression, and even suicideor acute psychosis. Interferon therapy has also been associated withrelapse in people with a previous history of drug or alcohol abuse.

Side effects of Ribavarin treatment include histamine-like side effects(itching and nasal stuffiness) and anemia due to dose related hemolysisof red cells and histamine like side effects.

Taken together, the proceeding facts indicate a significant need foreffective small molecule inhibitors of hepatitis C virus replicationthat do not suffer from the above-mentioned drawbacks.

SUMMARY OF THE INVENTION

The invention provides compounds of Formula 1 (shown below) and includescertain azabenzofuran substituted thioureas and related compounds, whichpossess antiviral activity. The invention provides compounds of Formula1 that are potent and/or selective inhibitors of Hepatitis C virusreplication. The invention also provides pharmaceutical compositionscontaining one or more compound of Formula 1, or a salt, solvate, oracylated prodrug of such compounds, and one or more pharmaceuticallyacceptable carriers, excipients, or diluents.

The invention further comprises methods of treating patients sufferingfrom certain infectious diseases by administering to such patients anamount of a compound of Formula 1 effective to reduce signs or symptomsof the disease. These infectious diseases include viral infections,particularly HCV infections. The invention is particularly includesmethods of treating human patients suffering from an infectious disease,but also encompasses methods of treating other animals, includinglivestock and domesticated companion animals, suffering from aninfectious disease.

Methods of treatment include administering a compound of Formula 1 as asingle active agent or administering a compound of Formula 1 incombination with on or more other therapeutic agent.

A method of inhibiting HCV replication in vivo by administering apatient infected with HCV a concentration of a compound or salt ofFormula 1 that is sufficient to inhibit HCV replicon replication invitro, is also disclosed herein.

Thus in a first aspect the invention includes compounds of Formula 1:

and the pharmaceutically acceptable salt thereof.

The variables Ar, A₁, A₂, A₃, A₄, R₅, R₆, R₇, V, W, X, and Y carry thedefinitions set forth below.

X and W are independently O, S, NR, or absent, where R is hydrogen,optionally substituted C₁-C₆alkyl, or optionally substituted(aryl)C₀-C₄alkyl.

V is C₁-C₆ alkyl, C₂-C₆alkenyl, C₃-C₇cycloalkyl, or absent.

Y is C₁-C₆ alkyl, C₁-C₆ alkyl substituted with C₃-C₇cycloalkyl,C₂-C₆alkenyl, or C₃-C₇cycloalkyl, or Y is absent; wherein when V isabsent, W is absent.

A₁ is Nitrogen or CR₁; A₂ is Nitrogen or CR₂; A₃ is Nitrogen or CR₃; andA₄ is Nitrogen or CR₄; where 1 or 2 of A₁, A₂, A₃, or A₄ is Nitrogen.

R₁-R₄, when present, are independently chosen from: hydrogen, halogen,hydroxy, cyano, nitro, amino, acetyl, —NHCO₂, —NHSO₂, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy, and

C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C]-C₆alkoxy, mono- anddi-(C₁-C₆alkyl)amino, C₂-C₆alkanoyl, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl,C₁-C₄alkylsulfonyl, C₁-C₄alkylcarboxamide, mono- anddi(C₁-C₆alkyl)carboxamide, (C₃-C₈cycloalkyl)C₀-C₂alkyl, C₂-C₇monocyclicheterocycloalkyl, phenyl, pyridyl, and pyrimidinyl; each of which issubstituted with 0 to 5 substituents independently chosen from halogen,hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R₅ is hydrogen, halogen, hydroxy, amino, nitro, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₂haloalkyl, or C₁-C₂haloalkoxy.

R₆ and R₇ are independently hydrogen, or

R₆ and R₇ are independently C₁-C₆alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,each of which is substituted with 0 to 3 substituents independentlychosen from halogen, hydroxy, amino, C₁-C₄alkoxy, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy, or

R₆ and R₇ are joined to form a 5- to 7-membered saturated ormono-unsaturated heterocyclic ring optionally containing one additionalheteroatom chosen from N, S, and O, which 5- to 7-membered saturated ormono-unsaturated heterocyclic ring is substituted with 0 to 3substituents independently chosen from halogen, hydroxy, amino,C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy.

Ar is optionally substituted aryl or optionally substituted heteroaryl.

Certain compounds of Formula 1 disclosed herein exhibit good activity inan HCV replication assay, such as the HCV replicon assay set forth inExample 5, which follows. Preferred compounds of Formula 1 exhibit anEC₅₀ of about 10 micromolar or less, or more preferably an EC₅₀ of about1 micromolar or less; or still more preferably an EC₅₀ of about 500nanomolar or less in an HCV replicon assay.

DETAILED DESCRIPTION OF THE INVENTION

Chemical Description and Terminology

Prior to setting forth the invention in detail, it may be helpful toprovide definitions of certain terms to be used herein. Compounds of thepresent invention are described using standard nomenclature. Unlessdefined otherwise, all technical and scientific terms used herein havethe same meaning as is commonly understood by one of skill in the art towhich this invention belongs.

Formula 1 includes all subformulae thereof. For example Formula 1includes compounds of Formulae 2-12. On certain occasions compounds ofFormula 1 are referred to herein as azabenzofuran substituted thioureas.The term “azobenzofuran” is used to indicate a benzo analogue, asix-membered aromatic ring containing one or more nitrogen atom, fusedto a furanyl ring.

In certain situations, the compounds of Formula 1 may contain one ormore asymmetric elements such as stereogenic centers, stereogenic axesand the like, e.g. asymmetric carbon atoms, so that the compounds canexist in different stereoisomeric forms. These compounds can be, forexample, racemates or optically active forms. For compounds with two ormore asymmetric elements, these compounds can additionally be mixturesof diastereomers. For compounds having asymmetric centers, it should beunderstood that all of the optical isomers and mixtures thereof areencompassed. In addition, compounds with carbon-carbon double bonds mayoccur in Z- and E-forms, with all isomeric forms of the compounds beingincluded in the present invention. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis, synthesis from optically pure precursors, or by resolution ofthe racemates. Resolution of the racemates can also be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralHPLC column.

Where a compound exists in various tautomeric forms, the invention isnot limited to any one of the specific tautomers, but rather includesall tautomeric forms.

The invention includes compounds of Formula 1 having all possibleisotopes of atoms occurring in the compounds. Isotopes include thoseatoms having the same atomic number but different mass numbers. By wayof general example, and without limitation, isotopes of hydrogen includetritium and deuterium and isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

Certain compounds are described herein using a general formula thatincludes variables, e.g. Ar, V, W, X, Y, A₁-A₄, and R₅-R₇. Unlessotherwise specified, each variable within such a Formula 1 is definedindependently of other variables. Thus, if a group is said to besubstituted, e.g. with 0-2 R*, then said group may be substituted withup to two R* groups and R* at each occurrence is selected independentlyfrom the definition of R*. Also, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When the substituent is oxo (i.e., ═O), then 2hydrogens on the atom are replaced. When aromatic moieties aresubstituted by an oxo group, the aromatic ring is replaced by thecorresponding partially unsaturated ring. For example a pyridyl groupsubstituted by oxo is a pyridone. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulationinto an effective therapeutic agent.

The phrase “optionally substituted” indicates that such groups mayeither be unsubstituted or substituted at one or more of any of theavailable positions, typically 1, 2, 3, or 4 positions, by one or moresuitable groups such as those disclosed herein.

Suitable groups that may be present on a “substituted” position include,but are not limited to, e.g., halogen; cyano; hydroxyl; nitro; azido;alkanoyl (such as a C₂-C₆ alkanoyl group such as acyl or the like);carboxamido; alkyl groups (including cycloalkyl groups, having 1 toabout 8 carbon atoms, or 1 to about 6 carbon atoms); alkenyl and alkynylgroups (including groups having one or more unsaturated linkages andfrom 2 to about 8, or 2 to about 6 carbon atoms); alkoxy groups havingone or more oxygen linkages and from 1 to about 8, or from 1 to about 6carbon atoms; aryloxy such as phenoxy, napthyloxy, and5,6,7,8-tetrahydronapthyloxy; alkylthio groups including those havingone or more thioether linkages and from 1 to about 8 carbon atoms, orfrom 1 to about 6 carbon atoms; alkylsulfinyl groups including thosehaving one or more sulfinyl linkages and from 1 to about 8 carbon atoms,or from 1 to about 6 carbon atoms; alkylsulfonyl groups including thosehaving one or more sulfonyl linkages and from 1 to about 8 carbon atoms,or from 1 to about 6 carbon atoms; aminoalkyl groups, which may have asingle nitrogen atom or more than one nitrogen atoms, and from 1 toabout 8, or from 1 to about 6 carbon atoms; aryl having 6 or morecarbons and one or more rings, (e.g., phenyl, biphenyl, naphthyl, or thelike, each ring either substituted or unsubstituted aromatic); arylalkylhaving 1 to 3 separate or fused rings and from 6 to about 18 ring carbonatoms, with benzyl being an exemplary arylalkyl group; arylalkoxy having1 to 3 separate or fused rings and from 6 to about 18 ring carbon atoms,with benzyloxy being an exemplary arylalkoxy group; or a saturated,unsaturated, or aromatic heterocyclic group having 1 to 3 separate orfused rings with 3 to about 8 members per ring and at least one ringhaving one or more N, O or S atoms.

A dash (“—”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example,—(CH₂)C₃-C₈cycloalkyl is attached through carbon of the methylene (CH₂)group.

As used herein, “acetyl” is a group of the formula —(C═O)CH₃.

As used herein, “alkyl” includes both branched and straight chainsaturated aliphatic hydrocarbon groups, having the specified number ofcarbon atoms, generally from 1 to about 12 carbon atoms. The termC₁-C₈alkyl as used herein indicates an alkyl group having from 1 toabout 8 carbon atoms. When C₀-C_(n) alkyl is used herein in conjunctionwith another group, for example, (aryl)C₀-C₄ alkyl, the indicated group,in this case aryl, is either directly bound by a single covalent bond(C₀), or attached by an alkyl chain having the specified number ofcarbon atoms, in this case from 1 to about 4 carbon atoms. Examples ofalkyl include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl.Alkyl groups described herein typically have from 1 to about 12 carbonsatoms. Preferred alkyl groups are lower alkyl groups, those alkyl groupshaving from 1 to about 8 carbon atoms, from 1 to about 6 carbon atoms,or from 1 to about 4 carbons atoms e.g. C₁-C₈, C₁-C₆, and C₁-C₄ alkylgroups.

“Alkenyl” as used herein, indicates a straight or branched hydrocarbonchain comprising one or more unsaturated carbon-carbon bonds, which mayoccur in any stable point along the chain. Alkenyl groups describedherein typically have from 2 to about 12 carbons atoms. Preferredalkenyl groups are lower alkenyl groups, those alkenyl groups havingfrom 2 to about 8 carbon atoms, e.g. C₂-C₈, C₂-C₆, and C₂-C₄ alkenylgroups. Examples of alkenyl groups include ethenyl, propenyl, andbutenyl groups.

“Alkynyl” as used herein, indicates a straight or branched hydrocarbonchain comprising one or more triple carbon-carbon bonds that may occurin any stable point along the chain, such as ethynyl and propynyl.Alkynyl groups described herein typically have from 2 to about 12carbons atoms. Preferred alkynyl groups are lower alkynyl groups, thosealkynyl groups having from 2 to about 8 carbon atoms, e.g. C₂-C₈, C₂-C₆,and C₂-C₄ alkynyl groups.

“Alkoxy” indicates an alkyl group as defined above with the indicatednumber of carbon atoms attached through an oxygen bridge (—O—). Examplesof alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy,3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and3-methylpentoxy.

“Alkenyloxy” indicates an alkenyl group as define above with theindicated number of carbon atoms attached through an oxygen bridge(—O—). Examples of alkenyloxy groups include, but are not limited to,prop-1-enyloxy and but-1-enyloxy.

“Alkanoyl” indicates an alkyl group as defined above, attached through aketo (—(C═O)—) bridge. Alkanoyl groups have the indicated number ofcarbon atoms, with the carbon of the keto group being included in thenumbered carbon atoms. For example a C₂alkanoyl group is an acetyl grouphaving the formula CH₃(C═O)—.

As used herein the term “alkanoyloxy” indicates an alkanoyl group asdefined above, having the indicated number of carbon atoms, attachedthrough an oxygen (—O—) bridge. Examples of alkanoyloxy groups includegroups of the formula CH₃(CH₂)(C═O)—O— and the like.

As used herein the term “mono- and/or di-alkylcarboxamide” refers togroups of formula (alkyl₁)-NH—(C═O)— and (alkyl₁)(alkyl₂)-N—(C═O)— inwhich the alkyl₁ and alkyl₂ groups are independently chosen alkyl groupsas defined above having the indicated number of carbon atoms. Monoand/or di-alkylcarboxamide also refers to groups of the formula—NH(C═O)(alkyl₁) and —N(alkyl₂)(C═O)(alkyl₁), carboxamide groups inwhich the point of attachment is the nitrogen atom, in which the alkyl₁and alkyl₂ groups are independently chosen alkyl groups as defined abovehaving the indicated number of carbon atoms.

As used herein the term “mono- and/or di-alkylsulfonamide” refers togroups of formula —NHSO₂(alkyl₁) and —N(alkyl₂) SO₂(alkyl₁) in which thealkyl₁ and alkyl₂ groups are independently chosen alkyl groups asdefined above having the indicated number of carbon atoms.

As used herein, “alkylsulfinyl” means alkyl-(SO)—, where the alkyl groupis an alkyl group as defined above having the defined number of carbonatoms. An exemplary alkylsulfinyl group is ethylsulfinyl.

As used herein, “alkylsulfonyl” means alkyl-(SO₂)—, where the alkylgroup is an alkyl group as defined above having the defined number ofcarbon atoms. An exemplary alkylsulfonyl group is methylsulfonyl.

As used herein, “alkylthio” means alkyl-S—, where the alkyl group is analkyl group as defined above having the defined number of carbon atoms.An exemplary alkylthio group is methylthio.

As used herein the term “alkoxycarbonyl” indicates an alkoxy group, asdefined above, having the indicated number of carbon atoms, attachedthrough a keto (—(C═O)—) bridge. The alkoxy moiety of the alkoxycarbonylgroup has the indicated number of carbon atoms; the carbon of the ketobridge is not included in this number. A C₃alkoxycarbonyl groupindicates for example, groups of the formula CH₃(CH₂)₂—O—(C═O)— or(CH₃)₂(CH)—O—(C═O)—.

As used herein “aminoalkyl” is an alkyl group as defined herein, havingthe indicated number of carbon atoms, and substituted with at least oneamino substituent (—NH₂). When indicated, aminoalkyl groups, like othergroups described herein, may be additionally substituted.

As used herein, the term “mono- and/or di-alkylamino” indicatessecondary or tertiary alkyl amino groups, wherein the alkyl groups areas defined above and have the indicated number of carbon atoms. Thepoint of attachment of the alkylamino group is on the nitrogen. Thealkyl groups are independently chosen. Examples of mono- anddi-alkylamino groups include ethylamino, dimethylamino, andmethyl-propyl-amino. “Mono- and/or dialkylaminoalkyl” groups are mono-and/or di-alkylamino groups attached through an alkyl linker having thespecified number of carbon atoms, for example a di-methylaminoethylgroup. Tertiary amino substituents may by designated by nomenclature ofthe form N—R—N—R′, indicating that the groups R and R′ are both attachedto a single nitrogen atom.

As used herein, the term “mono- and/or di-alkylaminoalkyl indicates amono- and/or di-alkylamino group as described above attached through analkyl linker having the specified number of carbon atoms.

As used herein, the term “aryl” indicates aromatic groups containingonly carbon in the aromatic ring or rings. Such aromatic groups may befurther substituted with carbon or non-carbon atoms or groups. Typicalaryl groups contain 1 or 2 separate, fused, or pendant rings and from 6to about 12 ring atoms, without heteroatoms as ring members. Whereindicated aryl groups may be substituted. Such substitution may includefusion to a 5 to 7-membered saturated cyclic group that optionallycontains 1 or 2 heteroatoms independently chosen from N, O, and S, toform, for example, a 3,4-methylenedioxy-phenyl group. Aryl groupsinclude, for example, phenyl, naphthyl, including 1-naphthyl and2-naphthyl, and bi-phenyl.

In the term “(aryl)alkyl”, aryl and alkyl are as defined above, and thepoint of attachment is on the alkyl group. “(Aryl)C₀-C₄alkyl” indicatesan aryl group that is directly attached via a single covalent bond(aryl)C₀alkyl or attached through an alkyl group having from 1 to about4 carbon atoms. The term (aryl)alkyl encompasses, but is not limited to,benzyl, phenylethyl, and piperonyl.

“Cycloalkyl” as used herein, indicates a monocyclic or multicyclicsaturated hydrocarbon ring group, having the specified number of carbonatoms, usually from 3 to about 10 ring carbon atoms. Monocycliccycloalkyl groups typically have from 3 to about 8 carbon ring atoms orfrom 3 to about 7 carbon ring atoms. Multicyclic cycloalkyl groups mayhave 2 or 3 fused cycloalkyl rings or contain bridged or cagedcycloalkyl groups. Cycloalkyl substituents may be pendant to asubstituted nitrogen or carbon atom, or when bound to a substitutedcarbon atom that may have two substituents a cycloalkyl group may beattached as a spiro group. Examples of cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, as well as bridgedor caged saturated ring groups such as norbomane or adamantane.

In the term “(cycloalkyl)alkyl”, cycloalkyl and alkyl are as definedabove, and the point of attachment is on the alkyl group. This termencompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl,and cyclohexylmethyl. (Cycloalkyl)C₀-C₂alkyl” indicates a cycloalkylgroup that is directly attached via a single covalent bond (i.e.(cycloalkyl)C₀alkyl) or attached through an alkyl group having from 1 toabout 2 carbon atoms.

As used herein the term “cycloalkylcarboxamide” refers to a cycloalkylgroup as defined above attached through an —NH—(C═O)— linker where thecycloalkyl group is covalently bound to the nitrogen atom.

“9- to 10-Membered bicyclic carbocyclic groups” refers to saturated,partially unsaturated, and aromatic ring groups have 2 rings, a total of9 or 10 ring atoms, with all ring members being carbon. Examples includenaphthyl, indanyl, and tetrahydronaphthyl. In certain embodimentsdescribed herein the 9- to 10-membered bicyclic carbocyclic group is agroup in which no more than one of the two rings is aromatic.

As used herein “Haloalkyl” indicates both branched and straight-chainalkyl groups having the specified number of carbon atoms, substitutedwith 1 or more halogen atoms, generally up to the maximum allowablenumber of halogen atoms. Examples of haloalkyl include, but are notlimited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, andpenta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined above attachedthrough an oxygen bridge.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, oriodo.

As used herein, “heteroaryl” indicates a stable 5- to 7-memberedmonocyclic aromatic ring which contains from 1 to 3, or preferably from1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atomsbeing carbon or a stable bicyclic or tricyclic system containing atleast one 5- to 7-membered aromatic ring which contains from 1 to 3, orpreferably from 1 to 2, heteroatoms chosen from N, O, and S, withremaining ring atoms being carbon. When the total number of S and Oatoms in the heteroaryl group exceeds 1, these heteroatoms are notadjacent to one another. It is preferred that the total number of S andO atoms in the heteroaryl group is not more than 2. It is particularlypreferred that the total number of S and O atoms in the aromaticheterocycle is not more than 1. Examples of heteroaryl groups include,but are not limited to, oxazolyl, pyranyl, pyrazinyl,pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl,pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl,thiophenyl, triazolyl, benzo[d]oxazolyl, benzofuranyl, benzothiazolyl,benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxynyl, furanyl,imidazolyl, indolyl, and isoxazolyl.

The term “heterocycloalkyl” indicates a saturated monocyclic groupcontaining from 1 to about 3 heteroatoms chosen from N, O, and S, withremaining ring atoms being carbon, or a saturated bicyclic ring systemhaving at least one N, O, or S ring atom with remaining atoms beingcarbon. Monocyclic heterocycloalkyl groups have from 4 to about 8 ringatoms, and more typically have from 5 to 7 ring atoms. Bicyclicheterocycloalkyl groups typically have from about five to about 12 ringatoms. In certain instances the size of a heterocycloalkyl groups isindicated by the number of ring carbon atoms the group contains. Forexample, a C₂-C₇heterocycloalkyl group contains from 2 to about 7 ringcarbon atoms with the remaining ring atoms, up to about 3 per ring,being chosen from N, O, and S. Preferred heterocycloalkyl groups includeC₂-C₇ monocyclic heterocycloalkyl groups and C₅-C₁₀ bicyclicheterocycloalkyl groups. Examples of heterocycloalkyl groups includemorpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl groups.

The term “5- to 7- membered saturated or mono-unsaturated heterocyclicring” indicates a cyclic group having from 5 to 7 ring atoms optionallycontaining one unsaturated bond, such as an alkenyl or alkynyl bond. 5-to 7-membered saturated or mono-unsaturated heterocyclic ring containfrom 1 to 3 heteroatoms independently selected from N, O, and S.Examples of such rings, which are saturated include piperazine,piperidine, morpholine, and pyrrolidine. Examples of such groups whichare mono-unsaturated include 1,2,3,6-tetrahydropyridine and2,3-dihydrooxazole.

The term “9- to 10-membered bicyclic heterocyclic groups” refers tosaturated partially unsaturated and aromatic ring groups have 2 rings, atotal of 9 or 10 ring atoms, having 1 to about 4 ring atomsindependently chosen from N, S, and O, with remaining ring atoms beingcarbon. Examples include quinolinyl, dihydroquinolinyl, and indolyl. Incertain embodiments described herein the 9- to 10-membered bicyclicheterocyclic group contains one ring Nitrogen atom, with remaining ringatoms being carbon.

As used herein an “imino” group is a group of the formula C═N, where thecarbon atom additionally contains two single bonds. An “alkylimino”group contains an alkyl group as defined above covalently bound to thenitrogen atom of an imino group. When specified the alkyl portion of analkylimino group may be optionally substituted.

As used herein a “thiocarbonyl” group is a group of the formula C═S,where the carbon atom additionally contains two single bonds.

“Pharmaceutically acceptable salts” includes derivatives of thedisclosed compounds wherein the parent compound is modified by makingnon-toxic acid or base salts thereof, and further refers topharmaceutically acceptable solvates of such compounds and such salts.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. The pharmaceuticallyacceptable salts of the present invention can be synthesized from aparent compound, a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, non-aqueous media like ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are preferred, where practicable.Lists of additional suitable salts may be found, e.g., in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,p. 1418 (1985).

The term “prodrugs” includes any compounds that become compounds ofFormula 1 when administered to a mammalian subject, e.g., upon metabolicprocessing of the prodrug. Examples of prodrugs include, but are notlimited to, acetate, formate and benzoate and like derivatives offunctional groups (such as alcohol or amine groups) in the compounds ofFormula 1.

The term “therapeutically effective amount” of a compound of thisinvention means an amount effective, when administered to a human ornon-human patient, to provide a therapeutic benefit such as anamelioration of symptoms, e.g., an amount effective to decrease thesymptoms of a viral infection, and preferably an amount sufficient toreduce the symptoms of an HCV infection. In certain circumstances apatient suffering from a viral infection may not present symptoms ofbeing infected. Thus a therapeutically effective amount of a compound isalso an amount sufficient to prevent a significant increase orsignificantly reduce the detectable level of virus or viral antibodiesin the patient's blood, serum, or tissues. A significant increase orreduction in the detectable level of virus or viral antibodies is anydetectable change that is statistically significant in a standardparametric test of statistical significance such as Student's T-test,where p<0.05.

A “replicon” as used herein includes any genetic element, for example, aplasmid, cosmid, bacmid, phage or virus, that is capable of replicationlargely under its own control. A replicon may be either RNA or DNA andmay be single or double stranded.

“Nucleic acid” or a “nucleic acid molecule” as used herein refers to anyDNA or RNA molecule, either single or double stranded and, if singlestranded, the molecule of its complementary sequence in either linear orcircular form. In discussing nucleic acid molecules, a sequence orstructure of a particular nucleic acid molecule can be described hereinaccording to the normal convention of providing the sequence in the 5′to 3′ direction.

Viral Inhibitors

The invention provides compounds and salts of Formula 1, also disclosedabove,

but wherein the variable Ar is defined as follows:

-   -   Ar is aryl or heteroaryl substituted with 0 to 5 substituents        independently chosen from:    -   (iii) halogen, hydroxy, cyano, nitro, oxo, C₁-C₂haloalkyl, and        C₁-C₂haloalkoxy, and    -   (iv) C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₁-C₈alkoxy,        C₂-C₈alkenyloxy, mono- and di-(C₁-C₈alkyl)amino, mono- and        di-(C₁-C₄alkyl)aminoC₁-C₄alkyl, C₂-C₈alkanoyl, C₂-C₈alkanoyloxy,        C₁-C₈alkoxycarbonyl, mono- and di-(C₁-C₈alkyl)carboxamide,        (C₃-C₇cycloalkyl)carboxamide, and C₁-C₈alkylthio, and    -   (v) -GR_(a).    -   G is chosen from —(CH₂)_(n)—, C₂-C₄alkenyl, C₂-C₄alkynyl,        —O(C═O)—, and —(CH₂)_(n)O(CH₂)_(m), —(CH₂)_(n)N(CH₂)_(m)—, where        n and m are independently 0, 1, 2, 3, or 4; and    -   R_(a) is chosen from C₃-C₈cycloalkyl, C₂-C₇monocyclic        heterocycloalkyl, mono-unsaturated 5- to 7-membered heterocyclic        rings, 9- to 10 membered bicyclic carbocyclic groups, 9- to        10-membered bicyclic heterocyclic groups containing 1 nitrogen        atom, aryl, and heteroaryl;

Each of (iv) and (v) is substituted with 0 to 5 substituentsindependently chosen from halogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy,mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, andphenyl.

The Variables V, W X, and Y

The invention includes compounds and salts of Formula 1 in which X isoxygen and Y is —CH₂—.

The invention includes compounds and salts of Formula 1 in which X isoxygen and Y is —CH₂CH₂—.

The invention also includes compounds and salts of Formula 1 in which Xand Y are absent.

The invention includes compounds and salts of Formula 1 in which V and Ware absent.

The invention includes compounds and salts of Formula 1 in which V isC₁-C₂alkyl and W is absent.

The Variables A₁-A₄

The invention includes compounds and salts of Formula 1, in which A₁ isNitrogen; A₂ is CR₂; A₃ is CR₃; and A₄ is CR₄, e.g., compounds and saltsof Formula 1-A:

The invention also includes compounds of Formula 1, in which A₁ is CR₁,A₂ is Nitrogen; A₃ is CR₃; and A₄ is CR₄, e.g., compounds and salts ofFormula 1-B:

The invention includes compounds of Formula 1, in which A₁ is CR₁; A₂ isCR₂; A₃ is Nitrogen; and A₄ is CR₄, e.g., compounds and salts of Formula1-C:

The invention includes compounds of Formula 1, in which A₁ is CR₁, A₂ isCR₂; A₃ is CR₃; and A₄ is Nitrogen, e.g., compounds and salts of Formula1-D:

The invention includes compounds of Formula 1, in which A₁ is Nitrogen;A₂ is CR₂; A₃ is Nitrogen; and A₄ is CR₄; e.g., compounds and salts ofFormula 1-E.

The invention includes compounds of Formula 1, in which A₁ is CR₁; Ar₂is Nitrogen; A₃ is CR₃; and A₄ is Nitrogen; e.g., compounds and salts ofFormula 1-F.

The invention includes compounds of Formula 1, in which A₁ is Nitrogen;A₂ is CR₂; A₃ is CR₃; and A₄ is Nitrogen; e.g., compounds and salts ofFormula 1-G.

The invention includes compounds and salts of Formula 1, wherein

-   -   R₁-R₄, when present, are independently chosen from    -   (i) hydrogen, halogen, hydroxy, cyano, nitro, amino, acetyl,        C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, and    -   (ii) C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino,        C₂-C₄alkanoyl, C₁-C₄alkylthio, C₃-C₇cycloalkyl, piperidinyl,        piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyridyl, and        pyrimidinyl; each of which is substituted with 0 to 5        substituents independently chosen from halogen, hydroxy,        C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino,        trifluoromethyl, and trifluoromethoxy.

The invention also includes compounds and salts of Formula 1, whereinR₁-R₄ when present, are independently chosen from hydrogen, halogen,hydroxy, cyano, nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy,C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₃-C₇cycloalkyl, piperidinyl, piperazinyl, morpholinyl,pyrrolidinyl, phenyl, pyridyl, and pyrimidinyl.

The invention also includes compounds and salts of Formula 1, whereinR₁-R₄ when present, are independently chosen from hydrogen, halogen,cyano, nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy,C₁-C₂alkyl, C₁-C₂alkoxy, C₃-C₇cycloalkyl, piperidinyl, pyrrolidinyl,phenyl, and pyridyl.

The Variable R₅

The invention includes compounds and salts of Formula 1, wherein R₅ ishydrogen or methyl.

The Variables R₆ and R₇

The invention includes compounds and salts of Formula 1, wherein R₆ andR₇ are independently hydrogen, or C₁-C₄alkyl, C₂-C₄alkenyl, orC₂-C₄alkynyl, each of which is substituted with 0 to 3 substituentsindependently chosen from halogen, hydroxy, amino, C₁-C₄alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The invention also includes compounds and salts of Formula 1, wherein R₆and R₇ are independently hydrogen, methyl, or ethyl.

The Variable Ar

The invention includes compounds and salts of Formula 1, wherein

-   -   Ar is phenyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, furanyl,        pyrazolyl, imidazolyl, thiazolyl, triazolyl, thiadiazolyl,        oxazolyl, isoxazolyl, benzofuranyl, benzothiazolyl,        benzothiophenyl, benzoxadiazolyl, benzo[d]oxazolyl,        dihydrobenzodioxynyl, indolyl, pyrazolopyrimidinyl,        thienylpyrazolyl, or benzopyranyl, each of which is substituted        with 0 to 5 substituents independently chosen from (iii), (iv),        and (v).

The invention also includes compounds and salts of Formula 1, wherein

-   -   Ar is phenyl or pyridyl; each of which is substituted with 0 to        5 substituents independently chosen from (iii), (iv), and (v).    -   Wherein:    -   (iii) represents halogen, hydroxy, cyano, nitro, oxo,        C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, and    -   (iv) represents C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl,        C₁-C₈alkoxy, C₂-C₈alkenyloxy, mono- and di-(C₁-C₈alkyl)amino,        mono- and di-(C₁-C₄alkyl)aminoC₁-C₄alkyl, C₂-C₈alkanoyl,        C₂-C₈alkanoyloxy, C₁-C₈alkoxycarbonyl, mono- and        di-(C₁-C₈alkyl)carboxamide, (C₃-C₇cycloalkyl)carboxamide, and        C₁-C₈alkylthio, and    -   (v) represents -GR_(a) where G is chosen from —(CH₂)_(n)—,        C₂-C₄alkenyl, C₂-C₄alkynyl, —O(C═O)—, —(CH₂)_(n)O(CH₂)_(m)—, and        —(CH₂)_(n)N(CH₂)_(m)—, where n and m are independently 0, 1, 2,        3, or 4; and R_(a) is chosen from C₃-C₈cycloalkyl,        C₂-C₇monocyclic heterocycloalkyl, mono-unsaturated 5- to        7-membered heterocyclic rings, 9- to 10 membered bicyclic        carbocyclic groups, 9- to 10- membered bicyclic heterocyclic        groups containing 1 nitrogen atom, aryl, and heteroaryl. Each of        which (iv) and (v) is substituted with 0 to 5 substituents        independently chosen from halogen, hydroxy, C₁-C₄alkyl,        C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl,        C₁-C₂haloalkoxy, and phenyl.

In certain embodiments the invention pertains to compounds and salts ofFormulae 2-12, shown below.

-   -   A₁-A₄ carry the definitions set forth above.    -   A₈, A₈′, A₉, and A₉′ are independently Nitrogen or CH, where 0,        1, or 2 of A₈, A₈′, A₉, and A₉′ are Nitrogen.    -   R₅ is hydrogen or methyl.    -   R₆ and R₇ are hydrogen or methyl.    -   R₁₀ is C₁-C₆alkyl.    -   R₁₁ represents 0 to 3 substituents independently chosen from        halogen, hydroxy, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, mono- and        di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy. These        substituents may replace any hydrogen atom on the rings to which        they are attached. For example when A₈ is CH, R₁₁ may replace        the hydrogen atom so that A₈ is CR₁₁.    -   R₁₂ represents 0 to 3 substituents independently chosen from        halogen, hydroxy, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, mono- and        di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; or in        compounds of Formula 4 to 7 and 9 to 10 R₁₂ may also represent a        5- to 7-membered oxygen containing ring containing 1 or 2 oxygen        atoms and fused to the phenyl to which it is attached. In        certain embodiments the 5- to 7 membered oxygen-containing ring        is a heterocycloalkyl ring.    -   R₁₃ and R₁₄ are independently hydrogen or methyl, and m is 0, 1,        or 2.    -   R₁₅ represents C₃-C₆alkoxy or C₃-C₆alkyl, each of which is        substituted with 0 to 3 substituents independently chosen from        halogen, hydroxy, C₁-C₃alkoxy, and mono- and        di-(C₁-C₅alkyl)amino.    -   R₁₆ is hydrogen or C₁-C₄alkyl.

In Formula 8, J is Nitrogen or CH; and Q is O, NR₁₆, or CH₂.

In Formulas 11 and 12, Q is absent, O, —CR₁₃R₁₄—, or NR₁₆, and R_(a) isa 9- to 10 membered bicyclic carbocyclic group or a 9- to 10- memberedbicyclic heterocyclic group containing 1 nitrogen atom, each of which issubstituted with 0 to 3 substituents independently chosen from halogen,hydroxy, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, trifluoromethyl andtrifluoromethoxy. In certain embodiments R_(a) is indanyl or quinolinyl,each each of which is substituted with 0 to 3 substituents independentlychosen from halogen, hydroxy, cyano, C₁-C₂alkyl, C₁-C₂alkoxy,trifluoromethyl and trifluoromethoxy.

Examples of compounds of Formulae 4 to 7 and 9 to 10 in which R₁₂ is a5- to 7-membered ring containing 1 or 2 oxygen atoms and fused to thephenyl to which it is attached include the following:

(A compound of Formula 4, in which R₁₂ is a 5 membered ring containing 1oxygen, fused to the phenyl to which it is attached)

(A compound of Formula 5, in which R₁₂ represents a methyl and a 5membered ring containing 2 oxygen atoms, fused to the phenyl to which itis attached)

(A compound of Formula 6, in which R₁₂ represents a methoxy and a 6membered ring, containing 2 oxygen atoms, fuised to the phenyl to whichit is attached)

(A compound of Formula 7, in which R₁₂ represents a 6 membered ringcontaining 1 oxygen atom, fused to the phenyl to which it is attached)

The invention includes compounds and salts of Formulae 2-12, above,wherein

-   -   R₁-R₄ when present, are independently chosen from hydrogen,        halogen, hydroxy, cyano, nitro, amino, acetyl, trifluoromethyl,        trifluoromethoxy, C₁-C₄alkyl, C₁-C₄alkoxy, mono- and        di-(C₁-C₄alkyl)amino, C₂-C₄alkanoyl, C₁-C₄alkylthio,        C₃-C₇cycloalkyl, piperidinyl, piperazinyl, morpholinyl,        pyrrolidinyl, phenyl, pyridyl, and pyrimidinyl.

The invention further includes compounds and salts of Formulae 2-12,above, wherein

-   -   R₁-R₄ when present, are independently chosen from hydrogen,        halogen, cyano, nitro, amino, acetyl, trifluoromethyl,        trifluoromethoxy, C₁-C₂alkyl, C₁-C₂alkoxy, C₃-C₇cycloalkyl,        piperidinyl, pyrrolidinyl, phenyl, and pyridyl.

The invention includes compounds and salts of Formulae 2-12, above, inwhich X and Y are both absent.

The invention also includes compounds and salts of Formulae 2-12 inwhich R₅, R₆, and R₇ are all hydrogen.

Compounds of Formula 1 having any combination of definitions for thevariables, e.g. A₁-A₄, R₅, R₆, R₇, V, W, X, Y, and Ar set forth hereinare included within the scope of the invention. For example, a compoundof Formula 1 in which A₁ is Nitrogen; A₂ is CR₂; A₃ is CR₃; and A₄ isCR₄, where R₂-R₄ are independently chosen from hydrogen, halogen, cyano,nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy, C₁-C₂alkyl,C₁-C₂alkoxy, C₃-C₇cycloalkyl, piperidinyl, pyrrolidinyl, phenyl, andpyridyl. And Ar is phenyl or pyridyl; each of which is substituted with0 to 5 substituents independently chosen from (iii), (iv), and (v).

Without wishing to be bound to any particular theory, it is believedthat the anti-HCV activity of compounds of Formula 1 is due to theirability to inhibit replication of the HCV replicon. Preferred compoundsof Formula 1 exhibit an EC₅₀ of about 10 micromolar or less, or morepreferably an EC₅₀ of about 1 micromolar or less; or an EC₅₀ of about500 nanomolar or less in an HCV replicon based assay of HCV replication,such as the assay provided in Example 5.

Preferred compounds of Formula 1 will have certain pharmacologicalproperties. Such properties include, but are not limited to oralbioavailability, low toxicity, low serum protein binding and desirablein vitro and in vivo half-lives.

The invention includes packaged pharmaceutical formulations. Suchpackaged formulations include a pharmaceutical composition containingone or more compounds or salts of Formula 1 in a container andinstructions for using the composition to treat a patient suffering fromHepatitis C infection (HCV infection).

Pharmaceutical Preparations

Compounds and salts of Formula 1 can be administered as the neatchemical, but are preferably administered as a pharmaceuticalcomposition or formulation. Accordingly, the invention providespharmaceutical formulations comprising a compound or pharmaceuticallyacceptable salt of Formula 1, together with one or more pharmaceuticallyacceptable carrier, excipients, adjuvant, diluent, or other ingredient.

Compounds of general Formula 1 may be administered orally, topically,parenterally, by inhalation or spray, sublingually, transdermally, viabuccal administration, rectally, as an ophthalmic solution, or by othermeans, in dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, excipients, adjuvants, andvehicles.

In addition to the subject compound, the compositions of the inventionmay contain a pharmaceutically acceptable carrier, one or morecompatible solid or liquid filler diluents or encapsulating substances,which are suitable for administration to an animal. Carriers must be ofsufficiently high purity and sufficiently low toxicity to render themsuitable for administration to the animal being treated. The carrier canbe inert or it can possess pharmaceutical benefits of its own. Theamount of carrier employed in conjunction with the compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound.

Exemplary pharmaceutically acceptable carriers or components thereof aresugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols suchas propylene glycol, glycerine, sorbitol, mannitol, and polyethyleneglycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents,such sodium lauryl sulfate; coloring agents; flavoring agents; tabletingagents, stabilizers; antioxidants; preservatives; pyrogen-free water;isotonic saline; and phosphate buffer solutions.

In particular, pharmaceutically acceptable carriers for systemicadministration include sugars, starches, cellulose and its derivatives,malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils,polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonicsaline, and pyrogen-free water. Preferred carriers for parenteraladministration include propylene glycol, ethyl oleate, pyrrolidone,ethanol, and sesame oil.

Optional active agents may be included in a pharmaceutical composition,which do not substantially interfere with the activity of the compoundof the present invention.

Effective concentrations of one or more of the compounds of theinvention including pharmaceutically acceptable salts, esters or otherderivatives thereof are mixed with a suitable pharmaceutical carrier,excipients, adjuvant, or vehicle. In instances in which the compoundsexhibit insufficient solubility, methods for solubilizing compounds maybe used. Such methods are known to those of skill in this art, andinclude, but are not limited to, using cosolvents, such asdimethylsulfoxide (DMSO), using surfactants, such as Tween, ordissolution in aqueous sodium bicarbonate. Derivatives of the compounds,such as salts of the compounds or prodrugs of the compounds may also beused in formulating effective pharmaceutical compositions.

Upon mixing or addition of the compound(s) of Formula 1, the resultingmixture may be a solution, suspension, emulsion or the like. The form ofthe resulting mixture depends upon a number of factors, including theintended mode of administration and the solubility of the compound inthe chosen carrier or vehicle. The effective concentration sufficientfor ameliorating the symptoms of the disease, disorder or conditiontreated and may be empirically determined.

The pharmaceutical compositions containing compounds of general Formula1 may be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agents, suchas sweetening agents, flavoring agents, coloring agents and preservingagents, in order to provide pharmaceutically elegant and palatablepreparations.

Oral formulations contain between 0.1 and 99% of a compound of theinvention and usually at least about 5% (weight %) of a compound of thepresent invention. Some embodiments contain from about 25% to about 50%or from 5% to 75% of a compound of invention.

Liquids Formulations

Compounds of the invention can be incorporated into oral liquidpreparations such as aqueous or oily suspensions, solutions, emulsions,syrups, or elixirs, for example. Moreover, formulations containing thesecompounds can be presented as a dry product for constitution with wateror other suitable vehicle before use. Such liquid preparations cancontain conventional additives, such as suspending agents (e.g.,sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin,hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel,and hydrogenated edible fats), emulsifying agents (e.g., lecithin,sorbitan monsoleate, or acacia), non-aqueous vehicles, which can includeedible oils (e.g., almond oil, fractionated coconut oil, silyl esters,propylene glycol and ethyl alcohol), and preservatives (e.g., methyl orpropyl p-hydroxybenzoate and sorbic acid).

Orally administered compositions also include liquid solutions,emulsions, suspensions, powders, granules, elixirs, tinctures, syrups,and the like. The pharmaceutically acceptable carriers suitable forpreparation of such compositions are well known in the art. Oralformulations may contain preservatives, flavoring agents, sweeteningagents, such as sucrose or saccharin, taste-masking agents, and coloringagents.

Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. Syrups and elixirs may beformulated with sweetening agents, for example glycerol, propyleneglycol, sorbitol or sucrose. Such formulations may also contain ademulcent.

Suspensions

For a suspension, typical suspending agents include methylcellulose,sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodiumalginate; typical wetting agents include lecithin and polysorbate 80;and typical preservatives include methyl paraben and sodium benzoate.

Aqueous suspensions contain the active material(s) in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents; may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol substitute, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan substitute.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example peanut oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Emulsions

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or peanut oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate.

Dispersible Powders

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.

Tablets and Capsules

Tablets typically comprise conventional pharmaceutically compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules (including time releaseand sustained release formulations) typically comprise one or more soliddiluents disclosed above. The selection of carrier components oftendepends on secondary considerations like taste, cost, and shelfstability.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Injectable and Parenteral Formulations

Pharmaceutical compositions may be in the form of a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents that have been mentioned above. The sterileinjectable preparation may also be sterile injectable solution orsuspension in a non-toxic parentally acceptable diluent or solvent, forexample as a solution in 1,3-butanediol. Among the acceptable vehiclesand solvents that may be employed are water, Ringer's solution, andisotonic sodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are useful inthe preparation of injectables.

Compounds of Formula 1 may be administered parenterally in a sterilemedium. Parenteral administration includes subcutaneous injections,intravenous, intramuscular, intrathecal injection or infusiontechniques. The drug, depending on the vehicle and concentration used,can either be suspended or dissolved in the vehicle. Advantageously,adjuvants such as local anesthetics, preservatives and buffering agentscan be dissolved in the vehicle. In compositions for parenteraladministration the carrier comprises at least about 90% by weight of thetotal composition.

Suppositories

Compounds of Formula 1 may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient that is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

Topical Formulations

Compounds of the invention may be formulated for local or topicalapplication, such as for topical application to the skin and mucousmembranes, such as in the eye, in the form of gels, creams, and lotionsand for application to the eye or for intracisternal or intraspinalapplication. Topical compositions of the present invention may be in anyform including, for example, solutions, creams, ointments, gels,lotions, milks, cleansers, moisturizers, sprays, skin patches, and thelike.

Such solutions may be formulated as 0.01% -10% isotonic solutions, pHabout 5-7, with appropriate salts. Compounds of the invention may alsobe formulated for transdermal administration as a transdermal patch.

Topical compositions containing the active compound can be admixed witha variety of carrier materials well known in the art, such as, forexample, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin Aand E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate,and the like.

Other materials suitable for use in topical carriers include, forexample, emollients, solvents, humectants, thickeners and powders.Examples of each of these types of materials, which can be used singlyor as mixtures of one or more materials, are as follows:

Emollients, such as stearyl alcohol, glyceryl monoricinoleate, glycerylmonostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetylalcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate,isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate,decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate,dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate,iso-propyl palmitate, iso-propyl stearate, butyl stearate, polyethyleneglycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachisoil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil,butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate,lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate;propellants, such as propane, butane, iso-butane, dimethyl ether, carbondioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylenechloride, iso-propanol, castor oil, ethylene glycol monoethyl ether,diethylene glycol monobutyl ether, diethylene glycol monoethyl ether,dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran; humectants,such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, solublecollagen, dibutyl phthalate, and gelatin; and powders, such as chalk,talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide,sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl arylammonium smectites, chemically modified magnesium aluminium silicate,organically modified montmorillonite clay, hydrated aluminium silicate,fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, andethylene glycol monostearate.

The compounds of the invention may also be topically administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Other Formulations

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol, and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethylcellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

Compositions for inhalation typically can be provided in the form of asolution, suspension or emulsion that can be administered as a drypowder or in the form of an aerosol using a conventional propellant(e.g., dichlorodifluoromethane or trichlorofluoromethane).

Additional Components

The compositions of the present invention may also optionally comprisean activity enhancer. The activity enhancer can be chosen from a widevariety of molecules that function in different ways to enhanceantimicrobial effects of compounds of the present invention. Particularclasses of activity enhancers include skin penetration enhancers andabsorbtion enhancers.

Pharmaceutical compositions of the invention may also contain additionalactive agents can be chosen from a wide variety of molecules, which canfunction in different ways to enhance the antimicrobial or therapeuticeffects of a compound of the present invention. These optional otheractive agents, when present, are typically employed in the compositionsof the invention at a level ranging from about 0.01% to about 15%. Someembodiments contain from about 0.1% to about 10% by weight of thecomposition. Other embodiments contain from about 0.5% to about 5% byweight of the composition.

Packaged Formulations

The invention includes packaged pharmaceutical formulations. Suchpackaged formulations include a pharmaceutical composition containingone or more compounds or salts of Formula 1 in a container andinstructions for using the composition to treat an animal (typically ahuman patient) suffering from a microorganism infection) or prevent amicroorganism infection in an animal.

In all of the foregoing the compounds of the invention can beadministered alone or as mixtures, and the compositions may furtherinclude additional drugs or excipients as appropriate for theindication.

Methods of Treatment

The invention includes methods of treating viral infections,particularly HCV infections, by administering an effective amount of oneor more compounds of Formula 1 to patient suffering from a viralinfection. An effective amount of a compound of Formula 1 may be anamount sufficient to reduce the symptoms of viral infection.Alternatively an effective amount of a compound of Formula 1 may be anamount sufficient to significantly reduce the amount of virus or viralantibodies detectable in a patient's tissues or bodily fluids.

Methods of treatment include administering an amount of a compound ofFormula 1 sufficient to reduce or relieve the jaundice, fatigue, darkurine, abdominal pain, loss of appetite, and nausea associated with HCVinfection.

Compounds of Formula 1 are thought to ameliorate the HCV disease processby virtue of their inhibition of the replication of the Hepatitis Cvirus. The compounds provided herein may be virucidal, in that theyactually kill the active virus, in addition to independently inhibitingviral replication. The provided compounds may also function throughmechanisms that involve a combination of virucidal activity andinhibition of replication.

Methods of treatment encompassed by the invention include administeringa compound of Formula 1 as the sole active agent and administering acompound of Formula 1 together with one or more other active agents,such another antiviral agent, particularly an anti-viral agent effectiveagainst HCV infection. The invention includes administering one or morecompounds of Formula 1 together with Peg-interferon, Peg-interferonalpha 2b, ribavarin (REBETOL), natural interferon, Albuferon,interferon-alpha-2b recombinant (INTRON) interferon beta-1a, IL-10,interferon gamma-1b, AMANTADINE, or ZADAXIM. Methods of Hepatitis Cinfection treatment particularly include administering a compound ofFormula 1 as the sole active agent and combination methods in which acompound of Formula 1 is administered in combination with ribavarinand/or an interferon, such as peg-interferon, or interferon-alpha-2brecombinant.

Methods of treatment also include inhibiting HCV replication in vivo, ina patient infected with HCV, by administering a sufficient concentrationof a compound of Formula 1 to inhibit HCV replicon replication in vitro.By “sufficient concentration” of a compound administered to the patientis meant the concentration of the compound available in the patient'ssystem to combat the infection. Such a concentration by be ascertainedexperimentally, for example by assaying blood concentration of thecompound, or theoretically, by calculating bioavailability.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of active agent.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most infectiousdiseases, a dosage regimen of 4 times daily or less is preferred and adosage regimen of 1 or 2 times daily or even less frequent isparticularly preferred.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Synthesis of Compounds

An illustration of the preparation of compounds of the present inventionis given in below in Example 1. Those having skill in the art willrecognize that the starting materials may be varied and additional stepsemployed to produce compound encompassed by the present invention.

EXAMPLES

Synthetic Scheme

A general method of preparing the compounds of the present invention isshown in Scheme I and further illustrated by the following syntheticexamples. As shown, an acid chloride 1 (or bromide) is reacted with ametal or ammonium thiocyanate in an appropriate solvent to provide thecorresponding acylisothiocyanate 2. Reaction of 2 with an appropriateprimary (R₆═H) or secondary amine 3 gives the acylthiourea 4. Furtheralkylation, when desirable, may be carried out on 4 to provide compoundsof general Formula 1. Alternatively, compounds of general Formula 1 maybe prepared by treatment of a primary (R₆═H) or secondary amide 5 withbase followed by reaction of the resulting anion with an appropriatelysubstituted isothiocyanate 6 to provide the acylthiourea 7. Furtheralkylation, when desirable, may be carried out on 7 to provide compoundsof general Formula 1.

The reaction to form the acid chloride is generally carried out in asolvent. Suitable solvents in this case are inert organic solvents thatdo not change under the reaction conditions. These preferably includeethers, such as diethyl ether or tetrahydrofuranyl, or tertiary butylmethyl ether; halogenohydrocarbons such as dichloromethane,trichloromethane, tetrachloromethane, 1,2-dichloroethane,trichloroethane, tetrachloroethane, 1,2-dichloroethane ortrichloroethylene, hydrocarbons such as benzene, xylene, toluene,hexane, heptane, cyclohexane or mineral oil fractions, nitromethane, oracetonitrile. It is also possible to employ mixtures of these solvents.

Reaction of the acid chloride with ammonium or potassium thiocyanate istypically carried out in a solvent in which the inorganic thiocyanate ismoderately soluble. In some cases, water may be added to increasesolubility. The percentage of water added may vary from one percent to90 percent, with 50% (v/v) typically being most preferred.

Other alkali thiocyanates, such as lithium thiocyanates, may beemployed. Lithium thiocyanate has increased solubility intetrahydrofuran and therefore may permit the use of smaller amounts ofaqueous components. Cesium, rubidium, strontium, and barium can all beused as counter ions to the thiocyanate, as is well known to onenormally skilled in the art.

Example 1

Preparation of4-[3-(Furo[3,2-C]Pyridin-2-Yl-Carbonyl)-Thioureido]-Benzoic Acid ButylEster (Compound 1)

Furo[3,2-c]pyridine-2-carbonyl chloride (161 mg, 1 mmol) is added to asolution of ammonium thiocyanate (200 mg, about 3 mmol) in acetone (5ml) and stirred at room temperature for 1 hour. Butyl 4-aminobenzoate(180 mg, 0.93 mmol) is added to the reaction mixture. Stirring iscontinued overnight at room temperature. Solvent is evaporated todryness and the residue diluted with 10% aqueous NaHCO₃. The product isfiltered, washed with water and methanol, and dried.

Example 2

Preparation of 3-Fluoro-4-(Pentyloxy)Benzenamine (Compound 2)

Example 3

Preparation of1-((2-Methylfuro[3,2-C]Pyridin-Yl-Carbonyl)-3-(3-Fluoro-4-Pentyloxy)-Phenyl)Thiourea(Compound 3)

Compound 3,1-((2-Methylfuro[3,2-c]pyridin-yl-carbonyl)-3-(3-fluoro-4-pentyloxy)-phenyl)thiourea,is prepared by the synthetic route outlined graphically above. Chemicalsare purchased from Aldrich Chemical Company and solvents are purchasedfrom Fisher Scientific. All reactions are carried out in an atmosphereof nitrogen or argon at indicated temperatures.

As shown above, furylacrylic acid (4, 5.0 g, 36.23 mmol) is treated withethyl chloroformate (4.83 ml, 50.72 mmol) in dry acetone (50 ml) in thepresence of triethyl amine (6.05 ml, 43.5 mmol). After stirring at roomtemperature for 1 hour, sodium azide (3.53 g, 53035 mmol) in water (10ml) is added at 0° C. and the suspension is stirred for 1 hour. Thereaction mixture is diluted with icy water (150 ml) and extracted withbenzene (70 ml×3). The organic layer is dried with anhydrous sodiumsulfate, filtered, and concentrated to a small volume (˜60 ml). Theresulting azide compound (5) in benzene is added into a diphenylmethane(40 ml) and tributylamine (7 ml) solution pre-heated to 180° C. Theaddition should be controlled so that the temperature doesn't drop below170° C. After the addition is complete (˜2.5 h), the reaction mixture iscooled to room temperature and allowed to stand over night. Theresulting yellow precipitate is collected by filtration and is washedwith hexanes to give furopyridone (6).

Furopyridone (6, 3.26 g, 24.15 mmol) is treated with phosphorusoxychloride (10 ml) at refluxing temperature for 3 hours. After cooling,the dark solution is poured into ice and basified with aqueous sodiumhydroxide to pH ˜9. The mixture is extracted with chloroform. Afterevaporation of the chloroform, the brown oil is applied to flash columnchromatography on silica gel to give chlorofuropyridine as yellowcrystalline solid (7).

Chlorofuropyridine (7, 1.27 g, 8.27 mmol) is treated with zinc (3.23 g,49.6 mmol) in acetic acid (20 ml) at refluxing temperature until thestarting material disappears (˜4 hours). The reaction is filtered toremove solid. The filtrate is concentrated and the residue is dissolvedin water. After basification with 1N sodium hydroxide, the mixture isextracted with methylene chloride. Evaporation leaves a yellow oil,which is purified with flash column chromatography on silica gel to givefuropyridine as a yellow oil (8).

Furopyridine (8, 0.71 g, 5.96 mmol) is treated with n-butyl lithium(2.5M in hexane, 2.86 ml, 7.15 mmol) in anhydrous THF (30 ml) at −78° C.After 30 minutes, dry carbon dioxide is passed through the reactionmixture and the temperature is allowed to rise gradually to roomtemperature in 3 hours. The mixture is concentrated to dryness. Theresidue is dissolved in water (˜10 ml) and extracted with ethyl acetate.The aqueous layer is acidified to pH˜3 with 1N HCl and kept in therefrigerator over night. The resulting precipitates are filtered anddried to give azabenzofuran carboxylic acid as a white powder (9)

Azabenzofuran carboxylic acid (8, 0.054 g, 0.33 mmol) is suspended inDCM (2 ml) and treated with oxalyl chloride (0.058 ml, 0.66 mmol) in thepresence DMF (1 drop). The reaction is stirred at 0° C. for 2 hoursuntil no more bubbles evolve. The reaction mixture is concentrated todryness to yield acid chloride 10, which is treated with ammoniumthiocyante (0.05 g, 0.66 mmol) in anhydrous acetone (3 ml) at roomtemperature for 1 hours. Acyl isothiocyante in acetone,3-fluoro-4-pentoxy aniline (0.0591 g, 0.30 mmol), which is synthesizedseparately as shown in Scheme 2, is added into this reaction mixture andthe mixture is stirred at room temperature for 2 hours. Acetone isevaporated on a rotoevaporator and the residue diluted with 10% sodiumbicarbonate (1 ml). The solid is filtered, washed with water, methanoland dried to give compound 12 as yellow powder (0.0958 g).

Compound 12 (0.0863 g, 0.215 mmol) is dissolved in methylene chloride (5ml) and HCl/ether (2.0M, 0.215 ml, 0.43 mmol) is added at 0° C. Afterstirring for 30 minutes, solvent is evaporated to give the finalproduct,1-((2-methylfuro[3,2-c]pyridin-yl-carbonyl)-3-(3-fluoro-4-pentyloxy)-phenyl)thiourea,as a yellow powder (3).

The product is characterized by NMR (Bruker, 300 MHz) and MS. NMR (¹H,CDCl₃): 0.99 (3H), 1.40-1.31 (m, 4H), 1.79-1.74 (m, 2H), 3.98 (t, 2H),6.91 (t, 1H), 7.22 (m, 1H), 7.57-7.50 (m, 2H), 7.74 (s, 1H), 8.64 (1H),9.06 (s, 1H), 9.33 (s, 1H, NH); 12.03 (s, 1H, NH); MS: APCI (FinniganMSQ single quadrupole): 402(M+1) 443 (M⁺+1+ACN).

Example 4

Preparation of Additional Compounds of Formula 1.

The compounds shown in Table 1 are prepared by methods disclosed inScheme 1 and in Examples 1-3. Certain compounds shown in Table 1 wereanalyzed via LC-MS. Retention times and masses of the M+1 ion are givenfor those compounds. Retention time (tR) is measured in a gradient thatincreases from 30-100% B in 3.00 minutes where Buffer A is 0.1%trifluoroacetic acid in water and buffer B is 0.1% trifluoroacetic acidin acetonitrile. An analytical Phenomenex Luna C₈ column was used with aflow rate of 2.5 ml/minute. All HPLC/MS analytical data were observed ata wavelength of 220 nm using a Gilson 151 UV/VIS detector followed by aThermoFinnigan Surveyor MSQ. STRUCTURE Name RT M + 1 13

1-((3-Methoxyfuro[3,2- b]pyridin-2-yl-carbonyl)-3-(4-pentyl)-phenyl)thiourea 14

1-((furo[2,3-b]pyridin-2-yl- carbonyl)-3-(3- benzyloxy)phenyl)-thiourea0.62 404 15

1-((Furo[2,3-b]pyridin-2-yl- carbonyl)-3-(3- phenyloxy)phenyl)-thiourea16

1-((Furo[2,3-b]pyridin-2-yl- carbonyl)-3-(4- (pentyloxy)phenyl)-thiourea17

1-((Furo[2,3-b]pyridin-2-yl- carbonyl)-3-((4-pentyl)phenyl)- thiourea368 18

1-(Furo[3,2-c]pyridine-2-yl- carbonyl)-3-((3- phenyloxy)phenyl)-thiourea19

1-(Furo[3,2-c]pyridine-2-yl- carbonyl)-3-((4- pentyloxy)phenyl)-thiourea1.73 391 20

1-(Furo[3,2-c]pyridine-2-yl- carbonyl)-3-((3-Fluro-4-piperidin-1-yl)phenyl)-thiourea 21

1-(Furo[3,2-c]pyridine-2-yl- carbonyl)-3-((3- benzyloxy)phenyl)-thiourea22

1-(Furo[3,2-c]pyridine-2-yl- carbonyl)-3-((4-pentyl)phenyl)- thiourea 23

1-(Furo[3,2-c]pyridine-2-yl- carbonyl)-3-((3-fluoro-4-pentyloxy)phenyl)-thiourea 24

1-(Furo[2,3-c]pyridine-2-yl- carbonyl)-3-((4- pentyloxy)phenyl)-thiourea25

1-(Furo[2,3-c]pyridine-2-yl- carbonyl)-3-((4-pentyl)phenyl)- thiourea 26

1-(7-Chloro-furo[2,3- c]pyridine-2-yl-carbonyl)-3-((3-benzyloxy)phenyl)-thiourea 1.02 438 27

1-(Furo[3,2-c]pyridine-2-yl- carbonyl)-3-((3- phenoxy)phenyl)-thioureahydrochloride 28

1-(Furo[3,2-c]pyridine-2-yl- carbonyl)-3-((3-fluoro-4-pentyloxy)phenyl)-thiourea hydrochloride 29

1-(Furo[3,2-c]pyridine-2-yl- carbonyl)-3-((4- pentyloxy)phenyl)-thioureahydrochloride 30

1-(4-Chloro-furo[3,2- c[pyridine-2-yl-carbonyl)-3-((3-phenoxy)-phenyl)-thiourea 31

1-(3-(benzyloxy)phenyl)-3-(4- chlorofuro[3,2-c]pyridine-2-carbonyl)thiourea 32

1-(4-Chloro-furo[3,2- c]pyridine-2-yl-carbonyl)-3-((4-pentyloxy)phenyl)-thiourea 33

1-(4-Chloro-furo[3,2- c]pyridine-2-yl-carbonyl)-3-((3-fluoro-4-pentyloxy)phenyl)- thiourea 34

1-(4-Chloro-furo[3,2- c]pyridine-2-yl-carbonyl)-3-((4-pentyl)phenyl)-thiourea 35

1-(4-Methoxy-furo[3,2- c]pyridine-2-yl-carbonyl)-3-((3-phenoxy)-phenyl)-thiourea 36

1-(4-Methoxy-furo[3,2- c]pyridine-2-yl-carbonyl)-3-((3-benzoxy)-phenyl)-thiourea 37

1-(4-methoxyfuro[3,2- c]pyridine-2-carbonyl)-3-(4-(pentyloxy)phenyl)thiourea 38

1-(4-methoxyfuro[3,2- c]pyridine-2-carbonyl)-3-(4- pentylphenyl)thiourea39

1-(4-Methoxy-furo[3,2- c]pyridine-2-yl-carbonyl)-3-((3-fluoro-4-pentyloxy)phenyl)- thiourea 40

1-(4-hydroxyfuro[3,2- c]pyridine-2-carbonyl)-3-(4-(pentyloxy)phenyl)thiourea 41

1-(3-(benzyloxy)phenyl)-3-(4- (dimethylamino)furo[3,2-c]pyridine-2-carbonyl)thiourea 42

1-(4-(dimethylamino)furo[3,2- c]pyridine-2-carbonyl)-3-(4-(pentyloxy)phenyl)thiourea 43

1-(4-(dimethylamino)furo[3,2- c]pyridine-2-carbonyl)-3-(4-pentylphenyl)thiourea 44

1-(4-(dimethylamino)furo[3,2- c]pyridine-2-carbonyl)-3-(3- fluoro-4-(pentyloxy)phenyl)thiourea 45

1-(furo[3,2-c]pyridine-2- carbonyl)-3 -(4- (octyloxy)phenyl)thiourea1.99 426 46

1-(furo[3,2-c]pyridine-2- carbonyl)-3-(4- octylphenyl)thiourea 2.10 41047

1-(furo[3,2-c]pyridine-2- carbonyl)-3-(4- (hexyloxy)phenyl)thiourea 1.77398 48

1-(furo[3,2-c]pyridine-2- carbonyl)-3-(4- hexylphenyl)thiourea 1.86 38249

1-(4-cyclohexylphenyl)-3- (furo[3,2-c]pyridine-2- carbonyl)thiourea 1.75380 50

1-(3-benzylphenyl)-3-(furo[3,2- c]pyridine-2-carbonyl)thiourea 1.58 38851

1-(3-phenoxyphenethyl)-3- (furo[3,2-c]pyridine-2- carbonyl)thiourea 1.65418 52

1-(4-phenyl-benzyl)-3- (furo[3,2-c]pyridine-2- carbonyl)thiourea 1.62388 53

1-(3-phenyl-phenyl)-3- (furo[3,2-c]pyridine-2- carbonyl)thiourea 1.57374 54

1-(4-benzylphenyl)-3-(furo[3,2- c]pyridine-2-carbonyl)thiourea 1.59 38855

1-(4-phenyl-phenyl)-3- (furo[3,2-c]pyridine-2- carbonyl)thiourea 1.59374 56

1-(furo[3,2-c]pyridine-2- carbonyl)-3-(4- phenoxyphenyl)thiourea 1.56390 57

1-(3-(4-phenyl- benzyloxy)phenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea 1.81 480 58

1-(3-(3,4- difluorobenzyloxy)phenyl)-3- (furo[3,2-c]pyridine-2-carbonyl)thiourea 1.61 440 59

1-(4-(3,4-dihydroisoquinolin- 2(1H)-yl)phenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea 1.43 429 60

1-(3-(2,3-dihydro-1H-inden-2- yloxy)phenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea 1.66 430 61

1-(furo[3,2-c]pyridine-2- carbonyl)-3-(3- phenethoxyphenyl)thiourea 1.64418 62

1-(furo[3,2-c]pyridine-2- carbonyl)-3-(4-(pentyloxy)-3-(trifluoromethyl)phenyl)thiourea 1.81 452 63

1-(4-butoxyphenyl)-3- (furo[3,2-c]pyridine-2- carbonyl)thiourea 1.60 37064

1-(furo[3,2-c]pyridine-2- carbonyl)-3-(4-(heptyloxy)-3-(trifluoromethyl)phenyl)thiourea 2.03 480 65

1-(furo[3,2-c]pyridine-2- carbonyl)-3-(3-(isoquinolin-3-ylmethoxy)phenyl)thiourea 66

1-(4-(cyclohexylmethoxy)-3- fluorophenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea 1.57 428 67

1-(7-chlorofuro[2,3-c]pyridine- 2-carbonyl)-3-(3- phenoxyphenyl)thiourea1.78 424 68

1-(furo[3,2-c]pyridine-2- carbonyl)-3-(3-methoxy-4-phenyl-phenyl)thiourea 0.85 404 69

1-(3-tert-butoxyphenyl)-3- (furo[3,2-c]pyridine-2- carbonyl)thiourea0.83 382

Example 5

Assay for Identifying Compounds which Inhibit HCV Replication

Compounds claimed herein are tested for the ability to inhibit viralreplication of the Hepatitis C replicon in cultured cells in which theHCV replicon construct has been incorporated. The HCV replicon systemwas described by Bartenschlager, et. al (Science, 285, pp. 110-113(1999)). The replicon system is predictive of in vivo anti-HCV activity;compounds that are active in humans uniformly evidence activity in thereplicon assay.

In this assay HCV replicon containing cells are treated with differentconcentrations of the test compound to ascertain the ability of the testcompound to suppress replication of the HCV replicon. As a positivecontrol, HCV replicon-containing cells are treated with differentconcentrations of interferon alpha, a known inhibitor of HCVreplication. The replicon assay system includes NeomycinPhosphotransferase (NPT) as a component of the replicon itself in orderto detect the transcription of replicon gene products in the host cell.Cells in which the HCV replicon is actively replicating have high levelsof NPT; the level of NPT is proportional to HCV replication. Cells inwhich the HCV replicon is not replicating also have low levels of NPTand thus do not survive when treated with Neomycin. The NPT level ofeach sample is measured using a captured ELISA.

A protocol for testing compounds for the ability to inhibit viralreplication of the Hepatitis C replicon cultured cells in which thereplicon construct has been incorporated, follows.

5A. HCV Replicon and Replicon Expression

The HCV genome consists of a single ORF that encodes a 3000 amino acidpolyprotein. The ORF is flanked on the 5′ side by an untranslated regionthat serves as an internal ribosome entry site (IRES) and at the 3′ sideby a highly conserved sequence necessary for viral replication (3′-NTR).The structural proteins, necessary for viral infection, are located nearthe 5′ end of the ORF. The non-structural proteins, designated NS2 toNS5B comprise the remainder of the ORF.

The HCV replicon contains, 5′-3′, the HCV-IRES, the neomycinphosphotransferase (neo) gene, the IRES of encephalomyocarditis virus,which directs translation of HCV sequences NS3 to NS5B, and the 3′-NTR.The sequence of the HCV replicon has been deposited in GenBank(Accession no. AJ242652).

The replicon is transfected into Huh-7 cells using standard methods suchas electroporation.

5B. Cell Maintenance

The equipment and materials include, but are not limited to, Huh-7 HCVreplicon-containing cells, maintenance media (DMEM (Dulbecco's modifiedEagle media) supplemented with 10% FBS, L-glutamine, non-essential aminoacids, penicillin (100 units/ml), streptomycin (100 micrograms/ml), and500 micrograms/ml of Geneticin (G418), screening media (DMEMsupplemented with 10% FBS, L-glutamine, non-essential amino acids,penicillin (100 units/ml) and streptomycin (100 micrograms/ml)), 96 welltissue culture plates (flat bottom), 96 well plates (U bottom for drugdilution), Interferon alpha for positive control, fixation reagent (suchas methanol:acetone), primary antibody (rabbit anti-NPTII), secondaryantibody: Eu—N1 1, and enhancement solution.

HCV replicon-containing cells support high levels of viral RNA repliconreplication when their density is suitable. Over-confluency causesdecreased viral RNA replication. Therefore, cells must be kept growingin log phase in the presence of 500 micrograms/ml of G418. Generally,cells should be passed twice a week at 1:4-6 dilution. Cell maintenanceis conducted as follows:

HCV replicon-containing cells are examined under a microscope to ensurethat cells growing well. Cells are rinsed once with PBS and 2 ml trypsinis added. The cell/trypsin mixture is incubated at 37° C. in a CO₂incubator for 3-5 minutes. After incubation 10 ml of complete media isadded to stop the trypsinization reaction. Cells are blown gently, putinto a 15 ml tube, and spun at 1200 rpm for 4 minutes. Thetrypsin/medium solution is removed. Medium (5 ml) is added and the cellsare mixed carefully. The cells are counted.

The cells are then seeded onto 96-well plates at a density of 6000-7500cells/100 microliters/well (6-7.5×105 cells/10 ml/plate). The plates arethen incubated at 37° C. in a 5% CO₂ incubator.

Cells are examined under a microscope approximated 24 hours afterseeding and prior to adding drugs. If counting and dilution wereperformed correctly, cells are 60-70% confluent and nearly all cellsshould attach and spread evenly in the well.

5C. Treatment of HCV-Replicon Containing Cells with Test Compound

HCV replicon-containing cells are rinsed with once PBS once; 2 mls oftrypsin are then added. Cells are incubated at 37° C. in a 5% CO₂incubator for 3-5 minutes. 10 mls of complete medium is added to stopthe reaction. Cells are blown gently, put into a 15 ml tube, and spun at1200 rpm for four minutes. The trypsin/medium solution is removed and 5mls of medium (500 ml DMEM (high glucose)) from BRL catalog #12430-054;50 mls 10% FBS, 5% Geneticin G418 (50 mg/ml, BRL catalog #10131-035), 5ml MEM non-essential amino acids (100×BRL #11140-050) and 5 ml pen-strep(BRL #15140-148) is added. The cells and media are mixed carefully

Cells are plated with screening medium (500 ml DMEM (BRL #21063-029), 50ml FBS (BRL #10082-147) and 5 ml MEM non-essential amino acid (BRL#11140-050) at 6000-7500 cells/100 μl/well of 96 well plate (6-7.5×105cells/10 ml/plate). Plates are placed into 37° C. 5% CO₂ incubatorovernight.

5D. Assay

The following morning, drugs (test compounds or interferon alpha) arediluted in 96 well U bottom plates with media or DMSO/media, dependingon the final concentration chosen for screening. Generally for 6concentrations of each test compounds ranging from 10 micromolar to 0.03micromolar are applied. 100 μl of the test compound dilution is placedin wells of the 96 well plate containing the HCV replicon cells. Mediawithout drug is added to some wells as a negative controls. DMSO isknown to affect cell growth. Therefore, if drugs diluted in DMSO areused, all wells, including negative control (media only) and positivecontrol (interferon alpha) wells, must contain the same concentration ofDMSO, for single dose screening. The plates are incubated at 37° C. in ahumidified 5% CO₂ environment for three days.

On day four, the NTPII assay is quantitated. The medium is poured fromthe plates and the plates are washed once in 200 μl of PBS. The PBS isthen decanted and the plates tapped in a paper towel to remove anyremaining PBS. Cells are fixed in situ with 100 μl/well of pre-cooled(−20° C.) methanol:acetone (1:1) and the plates are placed at −20° C.for 30 minutes.

The fixing solution is poured from the plates and the plates allowed toair-dry completely (approximately one hour). The appearance of the driedcell layer is recorded and the density of the cells in the toxic wellsis scored with the naked eye. Alternatively cell viability may beassessed using the MTS assay described below.

The wells are blocked with 200 μl of blocking solution (10% FBS; 3% NGSin PBS) for 30 minutes at room temperature. The blocking solution isremoved and 100 μl of rabbit anti-NPTII diluted 1:1000 in blockingsolution is added to each well. The plates are then incubated 45-60minutes at room temperature. After incubation, wells are washed sixtimes with PBS-0.05% Tween-20 solution. 100 μl of 1:15,000 dilutedEuropium (EU)-conjugated goat anti-rabbit in blocking buffer is added toeach well and incubated at room temperature for 30-45 minutes. Theplates are washed again and 100 μl of enhancement solution (Perkin Elmer#4001-0010) is added to each well. Each plate is shaken (approx. 30 rpm)in a plate shaker for three minutes. 95 μl is transferred from each wellto a black plate; the EU signal is quantitated in a Perkin-Elmer VICTORplate reader (EU-Lance).

Test Results:

Compounds shown in Table 1 have been tested in the above assay and foundto inhibit replication of the HCV replicon with EC₅₀ values of less than10 micromolar.

Example 6

Cytotoxicity Assays

To insure that the decrease in replicon replication is due to compoundactivity against the HCV replicon rather than nonspecific toxicityassays are used to quantitate compound cytotoxicity.

Example 6A

Cellular Protein Albumin Assay for Cytotoxicity

Cellular protein albumin measurements provide one marker ofcytotoxicity. The protein levels obtained from cellular albumin assaysmay also be used to provide a normalization reference for antiviralactivity of compounds. In the protein albumin assay HCVreplicon-containing cells are treated for three days with differentconcentrations of helioxanthin; a compound that is known to be cytotoxicat high concentrations. The cells are lysed and the cell lysate used tobind plate-bound goat anti-albumin antibody at room temperature (25° C.to 28° C.) for 3 hours. The plate is then washed 6 times with 1×PBS.After washing away the unbound proteins, mouse monoclonal anti-humanserum albumin is applied to bind the albumin on the plate. The complexis then detected using phosphatase-labeled anti-mouse IgG as a secondantibody.

Example 6B

MTS Assay for Cytotoxicity

Cell viability may also be determined by CELLTITER 96 AQUEOUS ONESolution Cell Proliferation Assay (Promega, Madison Wis.), acalorimetric assay for determining the number of viable cells. In thismethod, before fixing the cells, 10-20 μl MTS reagent is added to eachwell according to manufacturer's instructions, plates are incubated at37° C. and read at OD 490 nm. During the incubation period living cellscovert the MTS reagent to a formazan product which absorbs at 490 nm.Thus the 490 nm absorbance is directly proportional to the number ofliving cells in culture.

A direct comparison of the Cellular Album and MTS methods fordetermining cytotoxicity may be obtained as follows: Cells are treatedwith different concentrations of test compound or Helioxanthin for athree day-period. Prior to lysis for detection album as described above,the MTS reagent is added according to manufacturer's instruction to eachwell and incubate at 37 0C and read at OD 490 nm. The cellular albumquantitation is then performed as described above.

Example 7

Pharmaceutical Formulations

Examples 7A through 7G are examples of pharmaceutical compositionscontaining the compounds of Formula 1. The abbreviation “V.I.” standsfor the viral inhibitor compounds of Formula 1 of the present invention.

Example 7A

Oral Drops

5 grams of V.I. is dissolved in 5 ml of 2-hydroxypropanoic acid and 15ml polyethylene glycol at about 60° C. to about 80° C. After cooling toabout 30°-40° C., 350 ml polyethylene glycol is added and the mixturewas stirred well. A solution of 17.5 g sodium saccharin in 25 mlpurified water is then added. Flavor and polyethylene glycol q.s.(quantity sufficient) to a volume of 500 ml are added while stirring toprovide an oral drop solution comprising 10 mg/ml of V.I.

Example 7B

Capsules

20 grams of the V.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate are vigorously stirred together. The resultingmixture is subsequently filled into 1000 suitable hardened gelatincapsules, comprising each 20 mg of the active ingredient.

Example 7C

Film-Coated Tablets

Preparation of tablet core: A mixture of 10 grams of the V.I., 57 gramslactose and 20 grams starch is mixed well and thereafter humidified witha solution of 0.5 grams sodium dodecyl sulfate, and 1.0 gramspolyvinylpyrrolidone (KOLLIDON-K 90) in about 20 ml of water. The wetpowder mixture is sieved, dried, and sieved again. Then 100 gramsmicrocrystalline cellulose (AVICEL) and 15 grams hydrogenated vegetableoil (STEROTEX) are added. The whole is mixed well and compressed intotablets, giving 1000 tablets, each containing 10 mg of the activeingredient.

Coating: Ethyl cellulose (0.5 grams, ETHOCEL 22 CPS) in 15 ml ofdichloromethane is added to a solution of 1.0 grams methyl cellulose(Methocel 60 HG.RTM.) in 7.5 ml of denatured ethanol. Then 7.5 ml ofdichloromethane and 0.25 ml 1,2,3-propanetriol are added. Polyethyleneglycol (1.0 grams) is melted and dissolved in 7.5 ml of dichloromethaneand added to the cellulose-containing solution. Magnesium Octadecanoate(0.25 grams), 0.5 grams polyvinylpyrrolidone, and 3.0 ml of concentratedcolor suspension (OPASPRAY K-1-2109) are added and the whole mixturehomogenized. The tablet cores are coated with this mixture in a coatingapparatus.

Example 7D

Injectible Solutions

(i) 1.8 grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate are dissolved in about 0.5 L of boiling water. Aftercooling to about 50° C., 4 grams lactic acid, 0.05 grams propyleneglycol, and 4 grams of viral inhibitor are added while stirring. Thesolution is cooled to room temperature and supplemented with water forinjection q.s. giving a solution containing 4 mg/ml of V.I. The solutionis sterilized by filtration and filled in sterile containers.

(ii) 100.0 g of an acid salt of an V.I. of the invention is dissolved inboiling water. After cooling to about 50° C., 37.5 grams lactic acid(90% by weight) are added while stirring. The solution is cooled to roomtemperatutre and water is added to 1 L. The solution is sterilized byfiltration and filled in sterile containers.

(iii) 5.00 g of an acid salt of an V.I. of the invention is dissolved inboiling water. After cooling to about 50° C., 2.20 grams lactic acid(90% by weight) are added while stirring. The solution is cooled to roomtemperature and water is added to 100 ml.

Example 7E

Gel

A compound or salt of the invention may be formed as a gel for topicalapplication.

A gel is prepared by suspending V.I. (0.2 g-5.0 g) in benzyl alcohol atroom temperature. A mixture of hydroxypropyl cellulose (2.5) grams anddemineralized water (q.s. 100 g) is added to the suspension withstirring.

Example 7F

Cream

Phase I contains Sorbitan monostearate (2.0 g), Polyoxyethylene (20)sorbitan monostearate (1.5 g), Synthetic spermaceti (3.0 g) Cetylstearyl alcohol (10.0 g) and 2-Octyldodecanol (13.5 g). The phase Imixture is heated to 75° C., stirred and mixed.

Phase II contains V.I. (1.0 g). Phase II is added to phase I, stirredand suspended.

Phase III contains Benzyl alcohol (1.0 g) and demineralized water (q.s.100 g). Phase III is heated to 75° C. and added to phase II. The creamis mixed intensively and cooled slowly to room temperature, with furtherstirring. After cooling to room temperature the cream is homogenized.

Example 7G

Sprays

The active compound solutions or suspensions prepared according toExample 7D can also be processed to sprays. For this purpose, forexample, a 60 to 90% active compound solution is mixed with 20 to 40% ofthe usual propellants, for example N₂, N₂O, CO₂, propane, butane,halogenohydrocarbons and the like.

1. A compound of Formula 1

or a pharmaceutically acceptable salt thereof, wherein X and W areindependently O, S, NR, or absent, where R is hydrogen, optionallysubstituted C₁-C₆alkyl, or optionally substituted (aryl)C₀-C₄alkyl; V isC₁-C₆ alkyl, C₂-C₆alkenyl, C₃-C₇cycloalkyl, or absent; Y is C₁-C₆ alkyl,C₁-C₆alkyl substituted with C₃-C₇cycloalkyl, C₂-C₆alkenyl,C₃-C₇cycloalkyl, or Y is absent; wherein when V is absent, W is absent;A₁ is Nitrogen or CR₁; A₂ is Nitrogen or CR₂; A₃ is Nitrogen or CR₃; A₄is Nitrogen or CR₄; where 1 or 2 of A₁, A₂, A₃, or A₄ is Nitrogen;R₁-R₄, when present, are independently chosen from: (i) hydrogen,halogen, hydroxy, cyano, nitro, amino, acetyl, —NHCO₂, —NHSO₂,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, and (ii) C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, mono- and di-(C₁-C₆alkyl)amino,C₂-C₆alkanoyl, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl,C₁-C₄alkylcarboxamide, mono- and di-(C₁-C₆alkyl)carboxamide,(C₃-C₈cycloalkyl)C₀-C₂alkyl, C₂-C₇monocyclic heterocycloalkyl, phenyl,pyridyl, and pyrimidinyl; each of which is substituted with 0 to 5substituents independently chosen from halogen, hydroxy, C₁-C₄alkyl,C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy; R₅ is hydrogen, halogen, hydroxy, amino, nitro, cyano,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, or C₁-C₂haloalkoxy; R₆ and R₇are independently hydrogen, or R₆ and R₇ are independently C₁-C₆alkyl,C₂-C₆ alkenyl, or C₂-C₆ alkynyl, each of which is substituted with 0 to3 substituents independently chosen from halogen, hydroxy, amino,C₁-C₄alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, or R₆ and R₇ arejoined to form a 5- to 7-membered saturated or mono-unsaturatedheterocyclic ring optionally containing one additional heteroatom chosenfrom N, S, and O, which 5- to 7-membered saturated or mono-unsaturatedheterocyclic ring is substituted with 0 to 3 substituents independentlychosen from halogen, hydroxy, amino, C₁-C₄alkyl, C₁-C₄alkoxy, mono- anddi-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; and Ar isoptionally substituted aryl or optionally substituted heteroaryl.
 2. Acompound or salt of claim 1, wherein Ar is aryl or heteroaryl, each ofwhich is substituted with 0 to 5 substituents independently chosen from:(iii) halogen, hydroxy, cyano, nitro, oxo, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy, and (iv) C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl,C₁-C₈alkoxy, C₂-C₈alkenyloxy, mono- and di-(C₁-C₈alkyl)amino, mono- anddi-(C₁-C₄alkyl)aminoC₁-C₄alkyl, C₂-C₈alkanoyl, C₂-C₈alkanoyloxy,C₁-C₈alkoxycarbonyl, mono- and di-(C₁-C₈alkyl)carboxamide,(C₃-C₇cycloalkyl)carboxamide, and C₁-C₈alkylthio, and (v) -GR_(a) whereG is chosen from —(CH₂)_(n)—, C₂-C₄alkenyl, C₂-C₄alkynyl, —O(C═O)—, and—(CH₂)_(n)O(CH₂)_(m)—, —(CH₂)_(n)N(CH₂)_(m)—, where n and m areindependently 0, 1, 2, 3, or 4; and R_(a) is chosen fromC₃-C₈cycloalkyl, C₂-C₇monocyclic heterocycloalkyl, mono-unsaturated 5-to 7-membered heterocyclic rings, 9- to 10-membered bicyclic carbocyclicgroups, 9- to 10- membered bicyclic heterocyclic groups containing 1nitrogen atom, aryl, and heteroaryl; each of which (iv) and (v) issubstituted with 0 to 5 substituents independently chosen from halogen,hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and phenyl. 3-4. (canceled)
 5. Acompound or salt of claim 2 in which X and Y are absent.
 6. A compoundor salt of claim 5 wherein V and W are absent.
 7. A compound or salt ofclaim 5 in which V is C₁-C₂alkyl and W is absent.
 8. (canceled)
 9. Acompound or salt of claim 5 in which R₆ and R₇ are independentlyhydrogen, methyl, or ethyl.
 10. A compound or salt of claim 9 in whichA₁ is Nitrogen; A₂ is CR₂; A₃ is CR₃; and A₄ is CR₄.
 11. A compound orsalt of claim 9 in which A₁ is CR₁; A₂ is Nitrogen; A₃ is CR₃; and A₄ isCR₄.
 12. A compound or salt of claim 9 in which A₁ is CR₁; A₂ is CR₂; A₃is Nitrogen; and A₄ is CR₄.
 13. A compound or salt of claim 9 in whichA₁ is CR₁; A₂ is CR₂; A₃ is CR₃; and A₄ is Nitrogen. 14-17. (canceled)18. A compound or salt of claim 9 wherein R₁-R₄ when present, areindependently chosen from hydrogen, halogen, hydroxy, cyano, nitro,amino, acetyl, trifluoromethyl, trifluoromethoxy, C₁-C₄alkyl,C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₂-C₄alkanoyl,C₁-C₄alkylthio, C₃-C₇cycloalkyl, piperidinyl, piperazinyl, morpholinyl,pyrrolidinyl, phenyl, pyridyl, and pyrimidinyl.
 19. (canceled)
 20. Acompound or salt of claim 9 wherein R₅ is hydrogen or methyl.
 21. Acompound or salt of claim 2, wherein Ar is phenyl, pyridyl, pyrimidinyl,thienyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl,thiadiazolyl, oxazolyl, isoxazolyl, benzofuranyl, benzothiazolyl,benzothiophenyl, benzoxadiazolyl, benzo[d]oxazolyl,dihydrobenzodioxynyl, indolyl, pyrazolopyrimidinyl, thienylpyrazolyl, orbenzopyranyl, each of which is substituted with 0 to 5 substituentsindependently chosen from (iii) halogen, hydroxy, cyano, nitro, oxo,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, and (iv) C₁-C₈alkyl, C₂-C₈alkenyl,C₂-C₈alkynyl, C₁-C₈alkoxy, C₂-C₈alkenyloxy, mono- anddi-(C₁-C₈alkyl)amino, mono- and di-(C₁-C₄alkyl)aminoC₁-C₄alkyl,C₂-C₈alkanoyl, C₂-C₈alkanoyloxy, C₁-C₈alkoxycarbonyl, mono- anddi-(C₁-C₈alkyl)carboxamide, (C₃-C₇cycloalkyl)carboxamide, andC₁-C₈alkylthio, and (v) -GR_(a) where G is chosen from —(CH₂)_(n)—,C₂-C₄alkenyl, C₂-C₄alkynyl, —O(C═O)—, —(CH₂)_(n)O(CH₂)_(m)—, and—(CH₂)_(n)N(CH₂)_(m)—, where n and m are independently 0, 1, 2, 3, or 4;and R_(a) is chosen from C₃-C₈cycloalkyl, C₂-C₇monocyclicheterocycloalkyl, mono-unsaturated 5- to 7-membered heterocyclic rings,9- to 10 membered bicyclic carbocyclic groups, 9- to 10- memberedbicyclic heterocyclic groups containing 1 nitrogen atom, aryl, andheteroaryl; each of which (iv) and (v) is substituted with 0 to 5substituents independently chosen from halogen, hydroxy, C₁-C₄alkyl,C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, and phenyl.
 22. A compound or salt of claim 21, whereinAr is phenyl or pyridyl; each of which is substituted with 0 to 5substituents independently chosen from (iii), (iv), and (v).
 23. Acompound or salt of claim 1 of any of Formula 2 to 7 and Formula 9 to12,

Formula 2

Formula 3

Formula 4

Formula 5

Formula 6

Formula 7

Formula 9

Formula 10

Formula 11

Formula 12

wherein: A₈, A₈′, A₉, and A₉′ are independently Nitrogen or CH; where 0,1, or 2 of A₈, A₈′, A₉, and A₉′ are Nitrogen; Q is absent, O, —CR₁₃R₁₄—,or NR₁₆; R₅ is hydrogen or methyl; R₆ and R₇ are independently hydrogenor methyl; R₁₀ is C₁-C₈alkyl; and R₁₁ represents 0 to 3 substituentsindependently chosen from halogen, hydroxy, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy. R₁₂ represents 0 to 3 substituents independently chosenfrom halogen, hydroxy, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, mono- anddi-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and phenyl; orR₁₂ represents a 5- to 7-membered ring containing 1 or 2 oxygen atomsand fused to the phenyl to which it is attached; R₁₃ and R₁₄ areindependently chosen from hydrogen and methyl, and m is 1 or 2; R₁₅represents C₃-C₈alkoxy or C₃-C₈alkyl, each of which is substituted with0 to 3 substituents independently chosen from halogen, hydroxy,C₁-C₃alkoxy, and mono- and di-(C₁-C₅alkyl)amino, or R₁₅ represents(C₃-C₈cycloalkyl)C₀-C₂alkyl or (C₃-C₈cycloalkyl)C₀-C₂alkoxy; R₁₆ ishydrogen or C₁-C₄alkyl; and R_(a) is indanyl or quinolinyl, each ofwhich is substituted with 0 to 3 substituents independently chosen fromhalogen, hydroxy, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, trifluoromethyl andtrifluoromethoxy. 24-28. (canceled)
 29. A compound or salt of claim 1 ofFormula 8

A₈, A₈′, A₉, and A₉′ are independently Nitrogen or CH; where 0, 1, or 2of A₈, A₈′, A₉, and A₉′ are Nitrogen; J is Nitrogen or CH; Q is O, NR₁₆,or CH₂; R₅ is hydrogen or methyl; R₆ and R₇ are independently hydrogenor methyl; R₁₁ and R₁₂ each represent 0 to 3 substituents independentlychosen from halogen, hydroxy, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, mono- anddi-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; and R₁₆ ishydrogen or C₁-C₄alkyl. 30-38. (canceled)
 39. A compound or salt ofclaim 1, wherein the compound is4-[3-(Furo[3,2-c]pyridin-2-yl-carbonyl)-thioureido]-benzoic acid butylester;1-((3-Methoxyfuro[3,2-b]pyridin-2-yl-carbonyl)-3-(4-pentyl)-phenyl)thiourea;1-((furo[2,3-b]pyridin-2-yl-carbonyl)-3-(3-benzyloxy)phenyl)-thiourea;1-((Furo[2,3-b]pyridin-2-yl-carbonyl)-3-(3-phenyloxy)phenyl)-thiourea;1-((Furo[2,3-b]pyridin-2-yl-carbonyl)-3-(4-(pentyloxy)phenyl)-thiourea;1-((Furo[2,3-b]pyridin-2-yl-carbonyl)-3-((4-pentyl)phenyl)-thiourea;1-(Furo[3,2-c]pyridine-2-yl-carbonyl)-3-((3-phenyloxy)phenyl)-thiourea;1-(Furo[3,2-c]pyridine-2-yl-carbonyl)-3-((4-pentyloxy)phenyl)-thiourea;1-(Furo[3,2-c]pyridine-2-yl-carbonyl)-3-((3-Fluro-4-piperidin-1-yl)phenyl)-thiourea;1-(Furo[3,2-c]pyridine-2-yl-carbonyl)-3-((3-benzyloxy)phenyl)-thiourea;1-(Furo[3,2-c]pyridine-2-yl-carbonyl)-3-((4-pentyl)phenyl)-thiourea;1-(Furo[3,2-c]pyridine-2-yl-carbonyl)-3-((3-fluoro-4-pentyloxy)phenyl)-thiourea;1-(Furo[2,3-c]pyridine-2-yl-carbonyl)-3-((4-pentyloxy)phenyl)-thiourea;1-(Furo[2,3-c]pyridine-2-yl-carbonyl)-3-((4-pentyl)phenyl)-thiourea;1-(7-Chloro-furo[2,3-c]pyridine-2-yl-carbonyl)-3-((3-benzyloxy)phenyl)-thiourea;1-(Furo[3,2-c]pyridine-2-yl-carbonyl)-3-((3-phenoxy)phenyl)-thioureahydrochloride;1-(Furo[3,2-c]pyridine-2-yl-carbonyl)-3-((3-fluoro-4-pentyloxy)phenyl)-thioureahydrochloride;1-(Furo[3,2-c]pyridine-2-yl-carbonyl)-3-((4-pentyloxy)phenyl)-thioureahydrochloride;1-(4-Chloro-furo[3,2-c]pyridine-2-yl-carbonyl)-3-((3-phenoxy)-phenyl)-thiourea;1-(3-(benzyloxy)phenyl)-3-(4-chlorofuro[3,2-c]pyridine-2-carbonyl)thiourea;1-(4-Chloro-furo[3,2-c]pyridine-2-yl-carbonyl)-3-((4-pentyloxy)phenyl)-thiourea;1-(4-Chloro-furo[3,2-c]pyridine-2-yl-carbonyl)-3-((3-fluoro-4-pentyloxy)phenyl)-thiourea;1-(4-Chloro-furo[3,2-c]pyridine-2-yl-carbonyl)-3-((4-pentyl)phenyl)-thiourea;1-(4-Methoxy-furo[3,2-c]pyridine-2-yl-carbonyl)-3-((3-phenoxy)-phenyl)-thiourea;1-(4-Methoxy-furo[3,2-c]pyridine-2-yl-carbonyl)-3-((3-benzoxy)-phenyl)-thiourea;1-(4-methoxyfuro[3,2-c]pyridine-2-carbonyl)-3-(4-(pentyloxy)phenyl)thiourea;1-(4-methoxyfuro[3,2-c]pyridine-2-carbonyl)-3-(4-pentylphenyl)thiourea;1-(4-Methoxy-furo[3,2-c]pyridine-2-yl-carbonyl)-3-((3-fluoro-4-pentyloxy)phenyl)-thiourea;1-(4-hydroxyfuro[3,2-c]pyridine-2-carbonyl)-3-(4-(pentyloxy)phenyl)thiourea;1-(3-(benzyloxy)phenyl)-3-(4-(dimethylamino)furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(4-(dimethylamino)furo[3,2-c]pyridine-2-carbonyl)-3-(4-(pentyloxy)phenyl)thiourea;1-(4-(dimethylamino)furo[3,2-c]pyridine-2-carbonyl)-3-(4-pentylphenyl)thiourea;1-(4-(dimethylamino)furo[3,2-c]pyridine-2-carbonyl)-3-(3-fluoro-4-(pentyloxy)phenyl)thiourea;1-(furo[3,2-c]pyridine-2-carbonyl)-3-(4-(octyloxy)phenyl)thiourea;1-(furo[3,2-c]pyridine-2-carbonyl)-3-(4-octylphenyl)thiourea;1-(furo[3,2-c]pyridine-2-carbonyl)-3-(4-(hexyloxy)phenyl)thiourea;1-(furo[3,2-c]pyridine-2-carbonyl)-3-(4-hexylphenyl)thiourea;1-(4-cyclohexylphenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(3-benzylphenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(3-phenoxyphenethyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(4-phenyl-benzyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(3-phenyl-phenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(4-benzylphenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(4-phenyl-phenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(furo[3,2-c]pyridine-2-carbonyl)-3-(4-phenoxyphenyl)thiourea;1-(3-(4-phenyl-benzyloxy)phenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(3-(3,4-difluorobenzyloxy)phenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(4-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(3-(2,3-dihydro-1H-inden-2-yloxy)phenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(furo[3,2-c]pyridine-2-carbonyl)-3-(3-phenethoxyphenyl)thiourea;1-(furo[3,2-c]pyridine-2-carbonyl)-3-(4-(pentyloxy)-3-(trifluoromethyl)phenyl)thiourea;1-(4-butoxyphenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(furo[3,2-c]pyridine-2-carbonyl)-3-(4-(heptyloxy)-3-(trifluoromethyl)phenyl)thiourea;1-(furo[3,2-c]pyridine-2-carbonyl)-3-(3-(isoquinolin-3-ylmethoxy)phenyl)thiourea;1-(4-(cyclohexylmethoxy)-3-fluorophenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea;1-(7-chlorofuro[2,3-c]pyridine-2-carbonyl)-3-(3-phenoxyphenyl)thiourea;1-(furo[3,2-c]pyridine-2-carbonyl)-3-(3-methoxy-4-phenyl-phenyl)thiourea;or 1-(3-tert-butoxyphenyl)-3-(furo[3,2-c]pyridine-2-carbonyl)thiourea.40. A pharmaceutical composition comprising a compound or salt of claim1 together with a pharmaceutically acceptable carrier, diluent, orexcipient.
 41. A pharmaceutical composition of claim 40, wherein thecomposition is formulated as an injectable fluid, an aerosol, a cream, agel, a tablet, a pill, a capsule, a syrup, ophthalmic solution, or atransdermal patch.
 42. The pharmaceutical composition of claim 40 in acontainer and further comprising instructions for using the compositionto treat a patient suffering from Hepatitis C infection. 43-44.(canceled)
 45. A method of treating Hepatitis C infection comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound or salt claim
 1. 46. The method of claim45 comprising administering the compound or salt of claim 1 incombination with one or both of ribavarin and interferon. 47-50.(canceled)